RESUMEN
Solitary fibrous tumors (SFTs) are known for their heterogeneous morphology, characterized by a variety of cell shapes and different growth patterns. They can also arise in various anatomical locations, most commonly in extremities and deep soft tissues. Despite this diversity in morphology and location, all SFTs share a common molecular signature involving the NAB2::STAT6 gene fusion. Due to their unpredictable clinical behavior, establishing prognostic factors is crucial. This study aims to evaluate an orbital risk stratification system (RSS) proposed by Huang et al. for use in extraorbital SFTs using a database of 97 cases. The Huang model takes into consideration tumor size, mitotic figures, Ki-67 index, and dominant constituent cell (DCC) as key variables. Survival analysis confirmed the model's predictive value, with higher-risk scores being associated with poorer outcomes. However, in contrast to the orbital SFTs studied by Huang et al., our study did not find a correlation between tumor size and recurrence in extraorbital cases. While the Huang model performs slightly better than other RSS, it falls short on achieving statistical significance in distinguishing recurrence risk groups in extraorbital locations. In conclusion, this study validates the Huang RSS for use in extraorbital SFTs and underscores the importance of considering DCC, mitotic count, and Ki-67 together. However, we found that including tumor size in this model did not improve prognostic significance in extraorbital SFTs. Despite the benefits of this additional RSS, vigilant monitoring remains essential, even in cases classified as low-risk due to the inherent unpredictability of SFT clinical outcomes.
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Hemangiopericitoma , Neoplasias Orbitales , Síndrome de Trombocitopenia Febril Grave , Tumores Fibrosos Solitarios , Humanos , Neoplasias Orbitales/genética , Pronóstico , Antígeno Ki-67 , Proteínas Represoras/genética , Tumores Fibrosos Solitarios/diagnóstico , Tumores Fibrosos Solitarios/genética , Factor de Transcripción STAT6/genética , Medición de Riesgo , Biomarcadores de Tumor/genéticaRESUMEN
A healthy 32-year-old woman presented with the acute onset of left sided eye pain, upper eyelid fullness, and binocular diplopia during light weightlifting. Examination elevated intraocular pressure, proptosis, upper eyelid ptosis, and motility deficits. CT demonstrated a well-circumscribed, homogeneous-appearing extraconal mass in the superior left orbit. The patient underwent an urgent orbitotomy with the excision of a hemorrhagic mass. Histopathology showed a glomus tumor with atypical features and hemorrhagic infarction, best classified as having uncertain malignant potential. A B-Raf proto-oncogene V600E mutation was detected with immunohistochemistry, which suggests a more aggressive tumor behavior yet presents an opportunity for targeted primary or adjunctive therapy. This is the first reported case of a B-Raf proto-oncogene-mutant atypical glomus tumor arising in the orbit.
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Exoftalmia , Tumor Glómico , Neoplasias Orbitales , Femenino , Humanos , Adulto , Proteínas Proto-Oncogénicas B-raf/genética , Tumor Glómico/diagnóstico , Tumor Glómico/genética , Tumor Glómico/patología , Neoplasias Orbitales/diagnóstico , Neoplasias Orbitales/genética , Neoplasias Orbitales/patología , Órbita/patología , Exoftalmia/diagnósticoAsunto(s)
Neoplasias Orbitales , Receptor trkA , Humanos , Receptor trkA/genética , Receptor trkA/antagonistas & inhibidores , Neoplasias Orbitales/genética , Neoplasias Orbitales/cirugía , Inhibidores de Proteínas Quinasas/uso terapéutico , Masculino , Imagen por Resonancia Magnética , Femenino , Pirimidinas/uso terapéutico , Fibroblastos/patología , Tomografía Computarizada por Rayos X , Proteínas de Fusión Oncogénica/genética , PirazolesRESUMEN
PURPOSE: Metastatic ocular and orbital melanomas are extremely rare. The clinical characteristics and standard treatments for these patients are not fully established. MATERIALS AND METHODS: We retrospectively analyzed patients with metastatic ocular and orbital melanoma from Fudan University Shanghai Cancer Center and Eye & ENT Hospital of Fudan University between January 2012 and May 2022. RESULTS: Overall, 51 patients with metastatic ocular and orbital melanoma were included. The most common primary sites were uvea (73%), followed by conjunctiva (22%), lacrimal sac (4%), and orbit (2%). Patients with uveal melanoma (UM) had a significantly younger age (48 vs. 68 years, p < 0.001), higher incidence of liver metastases (89% vs. 9%, p<0.001), a lower incidence of lymph nodes metastases (16% vs. 46%, p = 0.043) and a lower incidence of BRAF mutation (0% vs. 55%, p<0.001) compared with patients with conjunctival melanoma (CM). The overall response rate of the first-line treatment was 18%. Three of the four patients with BRAF-mutated CM responded to dabrafenib and trametinib treatment. The median progression-free survival (PFS) and overall survival (OS) of first-line treatment were 5.1 and 11.9 months, respectively. Among patients with liver metastases, liver-directed treatment was correlated with better patient PFS (p < 0.001) and OS (p < 0.001) after adjusting for number of metastatic sites and primary sites. CONCLUSION: CM and UM have different characteristics. Patient with CM had a high incidence of BRAF mutation, and the treatment of BRAF and MEK inhibitors conferred clinical benefit. Liver directed therapies had a potential benefit in disease control in patients with liver metastases.
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Melanoma , Neoplasias Orbitales , Neoplasias Cutáneas , Humanos , Neoplasias Cutáneas/patología , Proteínas Proto-Oncogénicas B-raf/genética , Estudios Retrospectivos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Orbitales/tratamiento farmacológico , Neoplasias Orbitales/genética , China , Melanoma/tratamiento farmacológico , Melanoma/genética , Melanoma/patología , Pronóstico , MutaciónRESUMEN
PURPOSE: Programmed cell death protein 1 (PD-1) and DNA mismatch repair (MMR) deficiency play an important role in tumour progression and response to treatment.Both markers have been studied in some ocular tumours but little is known about these markers in orbital tumours. This pilot study reports on PD-L1 expression and MMR mutations using next generation sequencing (NGS) in specific orbital tumours. METHODS: We reviewed surgical specimens from patients with rhabdomyosarcoma, adenoid cystic carcinoma (ACC), pleomorphic adenoma (PA) and biopsy negative tissue from orbital tumours used as a control. immunohistochemistry (IHC) was performed on Formalin fixed paraffin embedded tissue using a PD-L1 antibody. DNA was extracted for targeted gene panel NGS of the MMR genes PMS2, MLH1, MSH6 and MSH2. RESULTS: The study included 17 orbital specimens. Scattered membrane PD-L1 staining was noted in 3/6 rhabdomyosarcoma specimens without an accompanying lymphocytic infiltrate. PD-L1 immunostaining was absent in 3/3 ACC, and 5/6 PA specimens. PD-L1 immunostaining was not detected in 2/2 control specimens. 4/17 samples shared the same pathogenic mutation in the MLH1 gene, including 3/6 rhabdomyosarcoma and 1/3 ACC samples. 1/6 PA samples had a mutation in MSH6. CONCLUSIONS: Our study demonstrated scattered, non-quantifiable or absent PD-L1 staining in a limited sample of orbital tumours suggesting that PD-1/PD-L1 inhibitor therapy may not be useful in treatment of malignant orbital tumours (rhabdomyosarcoma and ACC) when refractory to conventional therapy. Our pilot study suggest that PD-L1/MMR axis might not play a major role in the pathogenesis of primary orbital tumour.
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Neoplasias Orbitales , Rabdomiosarcoma , Apoptosis , Proteínas Reguladoras de la Apoptosis/genética , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Neoplasias Encefálicas , Neoplasias Colorrectales , Reparación de la Incompatibilidad de ADN/genética , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Humanos , Mutación , Síndromes Neoplásicos Hereditarios , Neoplasias Orbitales/genética , Proyectos Piloto , Receptor de Muerte Celular Programada 1/genética , Rabdomiosarcoma/genéticaRESUMEN
Melanocytoma is a benign tumor with histologic similarity to oculodermal melanocytosis, which can undergo malignant transformation in rare cases. Melanocytoma more commonly involves the optic disc, and few cases of orbital melanocytoma have been reported. Primary orbital melanoma is a rare malignancy known to arise from pigmentary conditions, although there is little information on this tumor arising from melanocytoma. The authors present a case of malignant transformation of orbital melanocytoma in the setting of ipsilateral oculodermal melanocytosis. This case illustrates histopathologic features associated with malignant transformation and highlights the significance of GNAQ, BAP1, and specific intrachromosomal alterations occurring in oculodermal melanocytosis and melanocytoma. The molecular markers observed in this case are of interest as they have overlap with those present in uveal melanoma. This case demonstrates a timeline of genetic and molecular alterations occurring in the malignant transformation of orbital melanocytoma.
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Melanoma , Disco Óptico , Neoplasias Orbitales , Neoplasias de la Úvea , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/patología , Humanos , Melanoma/complicaciones , Melanoma/diagnóstico , Melanoma/genética , Mutación , Disco Óptico/patología , Neoplasias Orbitales/complicaciones , Neoplasias Orbitales/diagnóstico , Neoplasias Orbitales/genéticaRESUMEN
This study aimed to analyze the role of the FcepsilonRI (FcεRI) signaling pathway in the pathogenesis of benign lymphoepithelial lesion of lacrimal gland (LGBLEL). Transcriptomic analysis was performed on LGBLEL and orbital cavernous hemangioma (CH) patients diagnosed via histopathology in Beijing Tongren Hospital, Capital Medical University, between July 2010 and October 2013. Four LGBLEL and three orbital CH patients, diagnosed between October 2018 and August 2019, were randomly selected as experimental and control groups, respectively. RT-PCR, immunohistochemical staining, and western blotting were used to verify genes and proteins related to the FcεRI signaling pathway. Transcriptomic analysis showed that the FcεRI signaling pathway was upregulated in the LGBLEL compared with the CH group. The mRNA expression levels of important genes including SYK, p38, JNK, PI3K, and ERK were significantly increased in the LGBLEL group (P = 0.0066, P = 0.0002, P = 0.0003, P < 0.0001, P < 0.0001, respectively). Immunohistochemical staining results showed that SYK, p38, and ERK were positively expressed in LGBLEL, while JNK and PI3K were not. The protein contents of P-SYK, P-p38, P-JNK, P-PI3K, and P-ERK were significantly higher in the LGBLEL than in the CH group (P = 0.0169, P = 0.0074, P = 0.0046, P = 0.0157, P = 0.0156, respectively). The FcεRI signaling pathway participates in the pathogenesis of LGBLEL.
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Enfermedades del Aparato Lagrimal/metabolismo , Enfermedades del Aparato Lagrimal/patología , Aparato Lagrimal/metabolismo , Aparato Lagrimal/patología , Receptores de IgE/metabolismo , Estudios de Casos y Controles , Dacriocistitis/genética , Dacriocistitis/metabolismo , Dacriocistitis/patología , Perfilación de la Expresión Génica , Redes Reguladoras de Genes , Hemangioma Cavernoso/genética , Hemangioma Cavernoso/metabolismo , Hemangioma Cavernoso/patología , Humanos , Inflamación/genética , Inflamación/metabolismo , Inflamación/patología , Enfermedades del Aparato Lagrimal/genética , Neoplasias Orbitales/genética , Neoplasias Orbitales/metabolismo , Neoplasias Orbitales/patología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Transducción de Señal/genéticaRESUMEN
Orbital (slow flow) cavernous venous hemangiomas (OCVH) are the most common benign orbital tumors in adults. The c-KIT is a tyrosine kinase receptor, which is expressed on several types of cells, is thought to play a key role in tumor pathogenesis. The purpose of this study was to evaluate the presence of the receptor c-KIT in OCVH. Our retrospective study examined 16 orbital cavernous venous hemangiomas from 16 cases operated on between 2006-2016 at Emek Medical Center. The mean tumor size was 18.4 mm. Symptoms appeared between 6 months and 22 years before operation. All specimens were analyzed for the c-KIT receptor through immunohistochemistry. The c-KIT was expressed by the endothelium in all 16 preparates. Staining was strong in two cases, moderate in six, and weak in eight cases, with no statistically significant correlation between staining and tumor size (p = 0.69) or the symptom duration (p = 0.15). We conclude that c-KIT may play an important role in the pathogenesis of OCVH. This pilot study is significant in that tumor-targeted therapy such as Imatinib Mesylate and Sunitinib may have a role in treating surgically complicated cases located in the orbital apex. A large multicenter collaborative study is necessary to examine the role of c-KIT in OCVH.
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Regulación Neoplásica de la Expresión Génica , Hemangioma Cavernoso/metabolismo , Neoplasias Orbitales/metabolismo , Proteínas Proto-Oncogénicas c-kit/biosíntesis , Adolescente , Adulto , Anciano , Niño , Femenino , Hemangioma Cavernoso/genética , Hemangioma Cavernoso/patología , Humanos , Masculino , Persona de Mediana Edad , Neoplasias Orbitales/genética , Neoplasias Orbitales/patología , Proteínas Proto-Oncogénicas c-kit/genética , Adulto JovenRESUMEN
ABSTRACT: Perivascular epithelioid cell tumors (PEComas) are infrequent mesenchymal neoplasms that have particular histological and immunohistochemical features. Only a few cases have been described in the eye and orbit. This report presents a 28-year-old man who consulted for a painless left orbital mass. With the presumptive diagnosis of cavernous hemangioma, a surgical excisional biopsy was performed. Histopathological examination showed a well-delimited tumor composed of epithelioid cells with an eosinophilic cytoplasm and oval nucleus. The tumor cells stained diffusely for HMB-45 and transcription factor E3 (TFE3) and were focally positive for actin. There was no reactivity to S100 or desmin. Genetic testing revealed a TFE3 rearrangement. Based on these results, an extremely rare orbital TFE3-rearranged PEComa was diagnosed. Although no recurrence was seen at last follow-up, a review of the literature shows experience is limited regarding orbital PEComas and their malignant potential. Further research is needed to establish management guidelines, their association with the tuberous sclerosis complex, and the role of genetic mutations such as TFE3 rearrangement.
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Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/genética , Neoplasias Orbitales/genética , Neoplasias Orbitales/patología , Neoplasias de Células Epitelioides Perivasculares/genética , Neoplasias de Células Epitelioides Perivasculares/patología , Adulto , Reordenamiento Génico/genética , Humanos , MasculinoRESUMEN
BACKGROUND: Neuroblastoma (NB) is the most common extracranial solid tumor in children. It is known for high heterogeneity and concealed onset. In recent years, the mechanism of its occurrence and development has been gradually revealed. The purpose of this study is to summarize the clinical characteristics of children with NB and abnormal chromosome 10, and to investigate the relationship between the number and structure of chromosome 10 abnormalities and NB prognosis. METHODS: Chromosome G-banding was used at the time of diagnosis to evaluate the genetics of chromosomes in patients with NB and track their clinical characteristics and prognosis. All participants were diagnosed with NB in the Medical Oncology Department of the Beijing Children's Hospital from May 2015 to December 2018 and were followed up with for at least 1 year. RESULTS: Of all 150 patients with bone marrow metastases, 42 were clearly diagnosed with chromosomal abnormalities. Thirteen patients showed abnormalities in chromosome 10, and chromosome 10 was the most commonly missing chromosome. These 13 patients had higher LDH and lower OS and EFS than children with chromosomal abnormalities who did not have an abnormality in chromosome 10. Eight patients had both MYCN amplification and 1p36 deletion. Two patients had optic nerve damage and no vision, and one patient had left supraorbital metastases 5 months after treatment. CONCLUSIONS: The results indicated that chromosome 10 might be a new prognostic marker for NB. MYCN amplification and 1p36 deletion may be related to chromosome 10 abnormalities in NB. Additionally, NB patients with abnormal chromosome 10 were prone to orbital metastases.
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Neoplasias de la Médula Ósea/secundario , Aberraciones Cromosómicas , Cromosomas Humanos Par 10 , Neuroblastoma/genética , Neuroblastoma/patología , Neoplasias de las Glándulas Suprarrenales/genética , Neoplasias de las Glándulas Suprarrenales/patología , Neoplasias de la Médula Ósea/genética , Preescolar , Cromosomas Humanos Par 1 , Femenino , Humanos , Lactante , Masculino , Neoplasias del Mediastino/genética , Neoplasias del Mediastino/patología , Proteína Proto-Oncogénica N-Myc/genética , Neoplasias Orbitales/genética , Neoplasias Orbitales/secundario , Pronóstico , Neoplasias Retroperitoneales/genética , Neoplasias Retroperitoneales/patologíaRESUMEN
Malignant epithelioid soft tissue tumors encompass a wide spectrum of lesions. Among them, Epithelioid Malignant Peripheral Nerve Sheath Tumors (MPNST) constitute a distinct subgroup, accounting for <5% of all MPNST. Epithelioid MPNST are infrequently associated with neurofibromatosis type 1, occasionally arise in a schwannoma and show diffuse S100 and CD34 expression, often combined with INI-1 loss. However, the molecular mechanisms underlying the tumorigenesis of epithelioid MPNST remain largely unknown. We describe a case of a 10-year-old girl with an epithelioid malignancy of the orbit. The tumor proved positive for S100, CD34 and SOX10, and, although INI-1 expression was maintained, the overall features suggested the possibility of an epithelioid MPNST, arising in an unusual location. NGS analysis revealed a novel in-frame BRD4-LEUTX fusion gene. LEUTX plays an important role in embryonal genome activation and its expression is mostly suppressed postnatally. We were able to detect increased levels of LEUTX transcript in the tumor, indicating that BRD4-LEUTX fusion leads to LEUTX re-activation. To our knowledge, this fusion has never been reported previously. Whether the current case represents an example of epithelioid MPNST or a distinct tumor entity remains to be determined.
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Biomarcadores de Tumor/genética , Proteínas de Fusión Oncogénica/genética , Neoplasias Orbitales/genética , Sarcoma/genética , Antígenos CD34/genética , Antígenos CD34/metabolismo , Biomarcadores de Tumor/metabolismo , Proteínas de Ciclo Celular/genética , Niño , Femenino , Proteínas de Homeodominio/genética , Humanos , Neoplasias Orbitales/patología , Proteínas S100/genética , Proteínas S100/metabolismo , Proteína SMARCB1/genética , Proteína SMARCB1/metabolismo , Factores de Transcripción SOXE/genética , Factores de Transcripción SOXE/metabolismo , Sarcoma/patología , Factores de Transcripción/genéticaRESUMEN
PURPOSE: To highlight the increasing importance of gene fusions in the diagnosis, prognosis, and therapy of ocular adnexal tumors. DESIGN: Perspective. METHODS: A focused review of gene fusions, their pathogenic mechanism, and gene fusion detection methods in lacrimal gland and primary orbital and ocular adnexal soft tissue tumors; reappraisal of diagnostic, prognostic, and therapeutic approach to ocular adnexal tumors in light of emerging molecular genetic data. RESULTS: The widespread implementation of fluorescence in situ hybridization and next-generation sequencing methods in pathology practice has led to identification of recurrent gene rearrangements and fusions in a variety of tumors. As a result, molecular genetic methods have become the gold standard for diagnosis of tumors with overlapping histology and immunophenotype, such as small round blue cell tumors. Identification of canonic gene fusions has led to development of sensitive and specific immunohistochemical markers, such as STAT6 in solitary fibrous tumor. In addition to diagnostic accuracy, gene fusions have prognostic implications, such as unfavorable prognosis of PAX3-FOXO1 fusion in alveolar rhabdomyosarcoma. Finally, recognition of gene fusions as a driving mechanism in neoplasia has led to development of U.S. Food and Drug Administration-approved targeted therapies, such as TRK inhibitors for NTRK fusion-positive cancers. CONCLUSION: The discovery of recurrent gene fusions in various tumors, including those involving ocular adnexa, has led to a deeper insight into the molecular mechanisms of these neoplasms, revolutionizing our approach to their diagnosis, prognostication, and therapy.
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Neoplasias del Ojo/genética , Fusión Génica/genética , Enfermedades del Aparato Lagrimal/genética , Neoplasias Orbitales/genética , Neoplasias de los Tejidos Blandos/genética , Biomarcadores de Tumor/genética , Variaciones en el Número de Copia de ADN , Neoplasias del Ojo/diagnóstico , Reordenamiento Génico , Pruebas Genéticas/métodos , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Hibridación Fluorescente in Situ , Enfermedades del Aparato Lagrimal/diagnóstico , Neoplasias Orbitales/diagnóstico , Pronóstico , Neoplasias de los Tejidos Blandos/diagnósticoRESUMEN
PURPOSE: To compare the expression of cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) and lymphocyte activation gene-3 (LAG-3) in nodular and orbitally-invasive forms of basal cell carcinoma (BCC). METHODS: Immunohistochemical staining for CTLA-4 and LAG-3 was performed on the pathology specimens of BCC from orbital exenteration and nodular forms. The numbers of positively-staining cells/×40 field were counted across 5 consecutive fields of each specimen and statistical analysis was performed to calculate the difference in expression between the 2 groups. RESULTS: Nine cases of orbitally-invasive BCC and 6 cases of nodular BCC were studied. The mean numbers of CTLA-4-positively staining cells were 11.51 cells/×40 field (median = 6.60 cells/×40 field, range = 0.4-31.8 cells/×40 field) in invasive BCC and 0.90 cells/×40 field (median = 0.60 cells/×40 field, range = 0.0-2.8 cells/×40 field) in nodular specimens. The difference between the 2 groups was statistically significant (p = 0.0030). The mean number of LAG-3-positively staining cells was 0.58 cells/×40 field (median = 0.0, range = 0.0-2.8 cells/×40 field) in invasive BCC and 3.13 cells/×40 field (median = 0.0, range = 0.0-18.18 cells/×40 field). There was no significant difference in LAG-3 positivity between tumor groups (p = 0.5564). CONCLUSIONS: CTLA-4 expression was enriched in orbitally invasive BCC compared with nodular forms of BCC, whereas LAG-3 expression did not differ between these entities. CTLA-4 mediated immune suppression may facilitate the development of orbitally invasive BCC. Treatment strategies that use existing medications to target CTLA-4 may decrease the requirement for orbital exenteration and provide enhanced survival outcomes.
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Antígenos CD/genética , Antígeno CTLA-4/genética , Carcinoma Basocelular/genética , Neoplasias Orbitales/genética , Neoplasias Cutáneas/genética , Humanos , Proteína del Gen 3 de Activación de LinfocitosAsunto(s)
Proteína del Grupo de Complementación N de la Anemia de Fanconi/genética , Tumores de Células Gigantes/secundario , Mutación , Órbita/patología , Neoplasias Orbitales/genética , Neoplasias de los Tejidos Blandos/diagnóstico , Adulto , Biopsia , Análisis Mutacional de ADN , ADN de Neoplasias/análisis , Proteína del Grupo de Complementación N de la Anemia de Fanconi/metabolismo , Femenino , Tumores de Células Gigantes/diagnóstico , Tumores de Células Gigantes/metabolismo , Humanos , Imagen por Resonancia Magnética , Metástasis de la Neoplasia , Neoplasias Orbitales/metabolismo , Neoplasias Orbitales/patología , Neoplasias de los Tejidos Blandos/genética , Neoplasias de los Tejidos Blandos/metabolismoRESUMEN
Although most commonly benign, neurofibromas (NFs) can have devastating functional and cosmetic effects in addition to the possibility of malignant transformation. In orbitofacial neurofibromatosis type 1, NFs may cause progressive, disfiguring tumors of the lid, brow, temple, face and orbit. The purpose of this study was to identify biological differences between orbitofacial NFs and those occurring at other anatomic sites. We used Illumina Methylation EPIC BeadChip to study DNA methylation differences between orbitofacial NFs (N = 20) and NFs at other sites (N = 4). Global methylation differences were detected between the two groups and the top differentially methylated genes were part of the HOX (Homebox) family of transcription factors (HOXC8, HOXC4, HOXC6, HOXA6 and HOXD4), which were hypomethylated in orbitofacial NFs compared to the non-orbital NFs. Conversely, LTF (lactoferrin) was relatively hypermethylated in orbitofacial NF compared to non-orbitofacial NF. HOXC8 protein levels were higher in orbitofacial plexiform NFs (p = 0.04). We found no significant differences in the expression of HOXC4, HOXA6, or HOXD4 between the two groups. HOXC8 mRNA levels were also higher in orbitofacial NFs and HOXC8 overexpression in a non-neoplastic human Schwann cell line resulted in increased growth. In summary, we identified gene methylation and expression differences between orbitofacial NF and NFs occurring at other locations. Further investigation may be warranted, given that the HOX family of genes play an important role during development, are dysregulated in a variety of cancers, and may provide novel insights into therapeutic approaches.
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Neoplasias Faciales/genética , Proteínas de Homeodominio/genética , Neurofibromatosis 1/genética , Neoplasias Orbitales/genética , Metilación de ADN/genética , Neoplasias Faciales/patología , Humanos , Neurofibromatosis 1/patología , Neoplasias Orbitales/patología , Estudios Retrospectivos , Factores de Transcripción/genética , TranscriptomaRESUMEN
Non-Hodgkin orbital lymphoma (NHOL) and idiopathic orbital inflammation (IOI) are common orbital conditions with largely unknown pathophysiology that can be difficult to diagnose. In this study we aim to identify serum miRNAs associated with NHOL and IOI. We performed OpenArray® miRNA profiling in 33 patients and controls. Differentially expressed miRNAs were technically validated across technology platforms and replicated in an additional cohort of 32 patients and controls. We identified and independently validated a serum miRNA profile of NHOL that was remarkably similar to IOI and characterized by an increased expression of a cluster of eight miRNAs. Pathway enrichment analysis indicated that the miRNA-cluster is associated with immune-mediated pathways, which we supported by demonstrating the elevated expression of this cluster in serum of patients with other inflammatory conditions. The cluster contained miR-148a, a key driver of B-cell tolerance, and miR-365 that correlated with serum IgG and IgM concentrations. In addition, miR-29a and miR-223 were associated with blood lymphocyte and neutrophil populations, respectively. NHOL and IOI are characterized by an abnormal serum miRNA-cluster associated with immune pathway activation and linked to B cell and neutrophil dysfunction.
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Inflamación/inmunología , Linfoma no Hodgkin/inmunología , MicroARNs/inmunología , Enfermedades Orbitales/inmunología , Neoplasias Orbitales/inmunología , Adulto , Anciano , Femenino , Humanos , Inflamación/genética , Linfoma no Hodgkin/genética , Masculino , Persona de Mediana Edad , Enfermedades Orbitales/genética , Neoplasias Orbitales/genéticaRESUMEN
Rhabdomyosarcoma (RMS) is the most common sarcoma of childhood and adolescence. Approximately 10% arise in the orbit, where the embryonal type is most common variant. The alveolar variant is less frequent and has a worse prognosis. Cytogenetic studies have revealed that most alveolar rhabdomyosarcomas have translocations involving the PAX and the FOX01 genes, giving rise to fusion genes that contribute to lack of differentiation and proliferation of the tumor cells. However, approximately 20% of alveolar rhabdomyosarcomas lack translocations and have been found to behave more similarly to embryonal cases. Histopathology remains the basis of diagnosis, but cytogenetic features and molecular signatures are becoming part of the routine analysis of RMS, since they determine not only prognosis, but also management and treatment regimens. A comprehensive review of the recent published literature in relation to orbital rhabdomyosarcomas and their cytogenetic features as well as clinical and therapeutic implications will be discussed.
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Análisis Citogenético/métodos , Citogenética/métodos , Neoplasias Orbitales , Rabdomiosarcoma , Humanos , Neoplasias Orbitales/genética , Neoplasias Orbitales/patología , Rabdomiosarcoma/genética , Rabdomiosarcoma/patologíaRESUMEN
PURPOSE: To analyze the genetic profile of 6 cases of primary orbital melanoma with clinicopathologic correlation. DESIGN: Retrospective noninterventional study to analyze the genetic profile of 6 cases of primary orbital melanoma and to correlate the genetic findings with prognosis and clinicopathologic features. Inclusion criteria were patients with primary orbital melanoma with no evidence of primary eyelid skin, conjunctival, uveal, or remote melanoma at extraocular sites. PARTICIPANTS: The study involved 6 primary orbital melanomas from 6 patients. Four patients were exenterated and 2 had incisional biopsies performed. METHODS: Clinical notes and radiologic records were assessed to ascertain clinical tumor behavior. Sections were stained with hematoxylin-eosin and exposed to immunohistochemistry for S100, MelA, HMB45, Sox10, and BAP1. Melanoma DNA was exposed to array comparative genomic hybridization to assess gross chromosomal copy number changes. Point mutation assessment and Sanger sequencing were performed for GNAQ, GNA11, BRAF, NRAS, pTERT, SF3B1, and EIF1AX. MAIN OUTCOME MEASURES: These were the presence of gross chromosomal copy number changes and the presence of mutations in GNAQ, GNA11, BRAF, NRAS, pTERT, SF3B1, and EIF1AX; the presence of metastases and time period between diagnosis and death from melanoma; and correlation between the tumor genetic profile and the clinical behavior of the tumor. RESULTS: One of the 6 cases was clinically associated with oculodermal melanocytosis. Of the 6 patients, 3 died of melanoma metastases and 1 of unrelated causes; 2 remain alive at last review. Three of the 6 cases were histologically associated with a benign precursor lesion. All melanomas expressed S100, MelA, HMB45, and Sox10. One patient showed loss of BAP1 nuclear staining. The most frequent chromosomal gains across the 6 cases, in order of frequency, were 6p, 8q, 17q, 6q, and 20p. The most frequently lost regions were 1p, 9p, 16q, and 17p. One patient showed monsomy 3 and gain of 8q (and showed the BAP1 loss). Mutations were found in GNAQ (1 case), GNA11 (1 case), SF3B1 (2 cases), NRAS (2 cases), and pTERT (2 cases). CONCLUSIONS: The data point to 2 genetic groups for primary orbital conjunctiva melanoma-like and a uveal melanoma-like group. A larger study would help confirm this suggestion.
Asunto(s)
Melanoma/genética , Neoplasias Orbitales/genética , Adulto , Anciano , Anciano de 80 o más Años , Hibridación Genómica Comparativa , Análisis Mutacional de ADN , Factor 1 Eucariótico de Iniciación/genética , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mutación , Factores de Empalme de ARN/genética , Estudios Retrospectivos , Proteínas Supresoras de Tumor/genética , Ubiquitina Tiolesterasa/genéticaRESUMEN
Protein arginine methyltransferase 7 (PRMT7) is a member of a family of enzymes that catalyze the transfer of methyl groups from S-adenosyl-l-methionine to nitrogen atoms on arginine residues. Arginine methylation is involved in multiple biological processes, such as signal transduction, mRNA splicing, transcriptional control, DNA repair, and protein translocation. Currently, 10 patients have been described with mutations in PRMT7. The shared findings include: hypotonia, intellectual disability, short stature, brachydactyly, and mild dysmorphic features. We describe the prenatal, postnatal, and pathological findings in two male sibs homozygote for a mutation in PRMT7. Both had intrauterine growth restriction involving mainly the long bones. In addition, eye tumor was found in the first patient, and nonspecific brain calcifications and a systemic venous anomaly in the second. The pregnancy of the first child was terminated and we describe the autopsy findings. The second child had postnatal growth restriction of prenatal onset, hypotonia, strabismus, sensorineural hearing loss, genitourinary and skeletal involvement, and global developmental delay. He had dysmorphic features that included frontal bossing, upslanting palpebral fissures, small nose with depressed nasal bridge, and pectus excavatum. Our patients provide additional clinical and pathological data and expand the phenotypic manifestations associated with PRMT7 homozygote/compound heterozygote mutations to include brain calcifications and delayed myelination, and congenital orbital tumor.