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Progression to aggressive secondary acute myeloid leukaemia (sAML) poses a significant challenge in the management of myeloproliferative neoplasms (MPNs). Since the physiopathology of MPN is closely linked to the activation of interferon (IFN) signalling and that AML initiation and aggressiveness is driven by leukaemia stem cells (LSCs), we investigated these pathways in MPN to sAML progression. We found that high IFN signalling correlated with low LSC signalling in MPN and AML samples, while MPN progression and AML transformation were characterized by decreased IFN signalling and increased LSC signature. A high LSC to IFN expression ratio in MPN patients was associated with adverse clinical prognosis and higher colony forming potential. Moreover, treatment with hypomethylating agents (HMAs) activates the IFN signalling pathway in MPN cells by inducing a viral mimicry response. This response is characterized by double-stranded RNA (dsRNA) formation and MDA5/RIG-I activation. The HMA-induced IFN response leads to a reduction in LSC signature, resulting in decreased stemness. These findings reveal the frequent evasion of viral mimicry during MPN-to-sAML progression, establish the LSC-to-IFN expression ratio as a progression biomarker, and suggests that HMAs treatment can lead to haematological response in murine models by re-activating dsRNA-associated IFN signalling.
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Leucemia Mieloide Aguda , Trastornos Mieloproliferativos , Humanos , Animales , Ratones , Trastornos Mieloproliferativos/tratamiento farmacológico , Trastornos Mieloproliferativos/genética , Trastornos Mieloproliferativos/complicaciones , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Pronóstico , Biomarcadores , Interferones/uso terapéuticoRESUMEN
Syphilis can mimic, clinically and microscopically, many other diseases. By microscopy, typically syphilis presents with plasma cell infiltration, admixed with lymphocytes and macrophages, in lichenoid and/or perivascular/perineural distribution pattern. When exuberant, this inflammatory infiltrate can mimic a lymphoproliferative disorder (LPD), notably plasma cell neoplasia or lymphoma. To date, about 12 cases of secondary syphilis, all but one in extraoral location, suggesting initially a LPD, have been published. Here, to our knowledge, we report an unusual case of intraoral primary syphilis initially suggesting LPD, notably lymphoid hyperplasia (pseudolymphoma); however, mucosa-associated lymphoid tissue (MALT) lymphoma and follicular lymphoma could not be disregarded. Polyclonality of plasma cells on immunohistochemistry, in strict clinical correlation, was essential to arrive at the correct diagnosis.
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Linfoma de Células B de la Zona Marginal , Trastornos Linfoproliferativos , Sífilis , Humanos , Sífilis/diagnóstico , Sífilis/patología , Trastornos Linfoproliferativos/diagnóstico , Trastornos Linfoproliferativos/patología , Linfoma de Células B de la Zona Marginal/patología , Linfocitos/patología , Diagnóstico DiferencialRESUMEN
The study evaluated the regenerative responses of the lacrimal functional unit (LFU) after lacrimal gland (LG) ablation. The LG of Wistar rats was submitted to G1) partial LG ablation, G2) partial ablation and transplantation of an allogeneic LG, or G3) total LG ablation, (n = 7-10/group). The eye wipe test, slit lamp image, tear flow, and histology were evaluated. RT-PCR analyzed inflammatory and proliferation mediators. The findings were compared to naïve controls after 1 and 2 months (M1 and M2). G3 presented increased corneal sensitivity, and the 3 groups showed corneal neovascularization. Histology revealed changes in the LG and corneal inflammation. In the LG, there was an increase in MMP-9 mRNA of G1 and G2 at M1 and M2, in RUNX-1 at M1 and M2 in G1, in RUNX-3 mRNA at M1 in G1, and at M2 in G2. TNF-α mRNA rose in the corneas of G1 and G2 at M2. There was an increase in the IL-1ß mRNA in the trigeminal ganglion of G1 at M1. Without changes in tear flow or evidence of LG regeneration, LG ablation and grafting are unreliable models for dry eye or LG repair in rats. The surgical manipulation extended inflammation to the LFU.
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Síndromes de Ojo Seco , Inflamación , Aparato Lagrimal , Ratas Wistar , Regeneración , Animales , Aparato Lagrimal/metabolismo , Aparato Lagrimal/patología , Aparato Lagrimal/cirugía , Síndromes de Ojo Seco/metabolismo , Síndromes de Ojo Seco/etiología , Síndromes de Ojo Seco/patología , Ratas , Inflamación/patología , Inflamación/metabolismo , Masculino , Córnea/metabolismo , Córnea/patología , Lágrimas/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/genética , Factor de Necrosis Tumoral alfa/metabolismo , Factor de Necrosis Tumoral alfa/genética , Interleucina-1beta/metabolismo , Interleucina-1beta/genética , Modelos Animales de EnfermedadRESUMEN
An 88-year-old male patient presented with a large mass on the left lateral bulbar conjunctiva. The tumor appeared two months after the resection of a conjunctival atypical fibroxanthoma (AFX) performed by a cornea specialist. Magnetic resonance imaging of the orbits showed deep orbital invasion along the lateral rectus muscle. The mass and the entire conjunctival sac were totally excised with lid-sparing orbital exenteration. Histopathological analysis confirmed that the mass was an extension of the AFX. Two weeks after surgery, large B-cell lymphoma was diagnosed in the oropharynx. Chemotherapy was initiated, and after seven months of follow-up, there was no recurrence of the AFX. The authors believe that this is the first report of orbital invasion by AFX.
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ABSTRACT: Lymphomatoid papulosis (LyP) belongs to the spectrum of primary cutaneous CD30 + lymphoproliferative disorders, characterized by chronic, recurrent, self-healing papules, small nodules, or ulcers. The clinicopathological features of LyP can mimic overt lymphomas. To date, about 27 intraoral LyP cases have been reported. Of them, only 2 cases were diagnosed as angioinvasive LyP (type E). Herein, we report a 24-year-old Brazilian man who presented a large ulcerated lesion on the hard palate with rapid evolution. Remarkably, there was no involvement of the skin or other mucous membranes. Microscopy revealed a lymphoid infiltrate constituted by medium-sized to large atypical cells, with angiocentric and angiodestructive features. The atypical cells showed immunopositivity for CD3, CD8, CD30, CD56, granzyme B, perforin, and focally for MUM1/IRF4. Ki-67 highlighted almost all atypical lymphoid cells, whereas EBER1/2 was negative. After 2 months of follow-up, the lesion healed completely. Although rare, LyP type E should be included in the differential diagnosis of oral ulcers.
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Papulosis Linfomatoide , Neoplasias Cutáneas , Masculino , Humanos , Adulto Joven , Adulto , Papulosis Linfomatoide/patología , Neoplasias Cutáneas/patología , Piel/patología , Diagnóstico Diferencial , Hueso Paladar/patologíaRESUMEN
Congenital opticmeningoceles was the term coined to describe large pseudocystic lesions of the intraorbital segment of the optic nerve. This extremely rare congenital anomaly was reported unilaterally only in nonsyndromic patients with fully developed eyes. The authors describe here a 10-month-old girl with a previous diagnosis of Joubert syndrome who presented with the same type of optic nerve malformation in OU. Molecular genetic analysis disclosed a pathogenic variant of the TMEM67 gene which is associated with various types of ciliopathies.
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Anomalías Múltiples , Anomalías del Ojo , Enfermedades Renales Quísticas , Femenino , Humanos , Lactante , Enfermedades Renales Quísticas/complicaciones , Enfermedades Renales Quísticas/diagnóstico , Enfermedades Renales Quísticas/genética , Anomalías Múltiples/diagnóstico , Anomalías Múltiples/genética , Anomalías Múltiples/patología , Cerebelo/anomalías , Anomalías del Ojo/complicaciones , Anomalías del Ojo/diagnóstico , RetinaRESUMEN
BACKGROUND: Psoriasis is a common cutaneous disease; however, information about psoriasis-related oral mucosal lesions is scarce in the literature. CASE DESCRIPTION: We report a case of a 73-year-old male patient with cutaneous and oral palatal alterations. An incisional biopsy of these lesions revealed psoriasis. CONCLUSION: The current case highlights the importance of a systematic examination of the oral cavity in psoriasis patients for the appropriate diagnosis and management on the control of these lesions.
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Mucosa Bucal , Psoriasis , Masculino , Humanos , Anciano , Mucosa Bucal/patología , Psoriasis/complicaciones , Psoriasis/diagnóstico , Psoriasis/patología , Diagnóstico Diferencial , BiopsiaRESUMEN
We report the case of a 64-year-old male patient with a 5 month history of proptosis, motility limitation and vision loss in OD. Visual acuity (VA) was 20/200 in OD and 20/20 in OS. CT showed a large, round, intraconal lesion, with bony density and no apparent connection to adjacent orbital walls. MRI showed a T1-weighted hypointense lesion surrounded by a contrast enhancing capsule. The orbital tumor was excised through a lateral orbitotomy revealing a nodular, round, osseous structure. Histological examination disclosed well-formed lamellar bone trabeculae, with no necrosis or mitosis figures. Immunohistochemical staining was negative for MDM2 and CDK4. After 3 years, there was no evidence of tumor recurrence and VA had improved to 20/30. Intraconal osteomas with no clear attachment to orbital walls are extremely rare. We are aware of a few reported cases in the lid, hand, thigh, tongue, pterygopalatine fossa and brain. To the authors' knowledge, this is the first report in English literature of an orbital intraconal osteoma without any visible relation to the orbital walls.
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Neoplasias Orbitales , Osteoma , Masculino , Humanos , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Osteoma/diagnóstico por imagen , Osteoma/cirugía , Neoplasias Orbitales/diagnóstico por imagen , Neoplasias Orbitales/cirugía , Tomografía Computarizada por Rayos X , Imagen por Resonancia MagnéticaRESUMEN
BACKGROUND: Myeloproliferative neoplasms (MPN) are disorders characterized by an alteration at the hematopoietic stem cell (HSC) level, where the JAK2 mutation is the most common genetic alteration found in classic MPN (polycythemia vera, essential thrombocythemia, and primary myelofibrosis). We and others previously demonstrated that metformin reduced splenomegaly and platelets counts in peripheral blood in JAK2V617F pre-clinical MPN models, which highlighted the antineoplastic potential of biguanides for MPN treatment. Phenformin is a biguanide that has been used to treat diabetes, but was withdrawn due to its potential to cause lactic acidosis in patients. AIMS: We herein aimed to investigate the effects of phenformin in MPN disease burden and stem cell function in Jak2V617F-knockin MPN mice. RESULTS: In vitro phenformin treatment reduced cell viability and increased apoptosis in SET2 JAK2V67F cells. Long-term treatment with 40 mg/kg phenformin in Jak2V617F knockin mice increased the frequency of LSK, myeloid progenitors (MP), and multipotent progenitors (MPP) in the bone marrow. Phenformin treatment did not affect peripheral blood counts, spleen weight, megakaryocyte count, erythroid precursors frequency, or ex vivo clonogenic capacity. Ex vivo treatment of bone marrow cells from Jak2V617F knockin mice with phenformin did not affect hematologic parameters or engraftment in recipient mice. CONCLUSIONS: Phenformin increased the percentages of LSK, MP, and MPP populations, but did not reduce disease burden in Jak2V617F-knockin mice. Additional studies are necessary to further understand the effects of phenformin on early hematopoietic progenitors.
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Trastornos Mieloproliferativos , Policitemia Vera , Animales , Médula Ósea , Modelos Animales de Enfermedad , Humanos , Janus Quinasa 2 , Ratones , Mutación , Trastornos Mieloproliferativos/tratamiento farmacológico , Fenformina/farmacología , Fenformina/uso terapéutico , Policitemia Vera/genéticaRESUMEN
Kimura's disease (KD) is a systemic inflammatory condition characterized by lymphadenopathy and subcutaneous nodules in the head and neck region. The lesions have a distinctive histopathological pattern formed by follicular hyperplasia, eosinophilic infiltrates, fibrosis, and vessel proliferation. The disease may occur at all ages but predominates among young males with autoimmune dysfunctions. Visceral and orbital involvement is uncommon. We report a girl with KD who developed bilateral enlargement of the lacrimal glands and a lesion in the left lateral ventricle of the brain indistinguishable from a central nervous system neoplasia. A biopsy of both the lacrimal gland and the lateral ventricle was consistent with KD.
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Hiperplasia Angiolinfoide con Eosinofilia , Dacriocistitis , Enfermedad de Kimura , Linfadenopatía , Hiperplasia Angiolinfoide con Eosinofilia/diagnóstico , Sistema Nervioso Central/patología , Niño , Dacriocistitis/diagnóstico , Dacriocistitis/etiología , Femenino , Humanos , MasculinoRESUMEN
We describe two cases of extensive indolent calvarial osteomyelitis after rhino-orbital-mucormycosis in diabetic patients previously diagnosed with COVID-19. Both patients presented with acute rhino-orbital symptoms about one month after being diagnosed with COVID-19. Treatment with intravenous liposomal Amphotericin B and prompt radical surgical debridement was instituted, but calvarial osteomyelitis ensued and persisted chronically despite maintenance of antifungal therapy and partial debridement of necrotic calvarial bone. The patients were discharged to continue antifungal therapy on a day-hospital regime. After more than 8 months of treatment, they remain with radiological signs of osteomyelitis but with no symptoms or intracranial extension of the infection. Calvarial indolent osteomyelitis secondary to mucormycosis is extremely rare, and little is known regarding its treatment. We believe it can be controlled with medical treatment and partial bony debridement although more studies are necessary to better define therapy.
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Cholesteatomas are frequent middle ear benign tumors of unknown etiology. Infectious agents have been considered as possible contributing factors in the pathogenesis of cholesteatomas. Aiming to investigate the presence of respiratory viruses in primary cholesteatoma tissues, 26 formalin-fixed paraffin-embedded primary cholesteatoma tissues obtained from patients seen at the of the Clinical Hospital of the University of São Paulo School of Medicine, in Ribeirão Preto, Brazil were tested by real-time polymerase chain reaction (PCR). Considering the PCR results, 35% of the tissues were positive for human rhinovirus (HRV), 15.3% for human enterovirus (EV), 3.8% for human metapneumovirus (HMPV), and 3.8% for human bocavirus (HBoV). Serial immunohistochemistry for virus antigens and cell surface markers evidenced that the viruses were associated with fibroblasts, dendritic cells, macrophages, B lymphocytes, CD4+ , and CD8+ T lymphocytes. These findings indicate for the first time the presence of active respiratory virus infection in primary cholesteatoma tissues, suggesting that persisting virus infection in the middle could play a role in the pathogenesis and evolution of cholesteatomas.
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Colesteatoma/virología , Enterovirus/aislamiento & purificación , Bocavirus Humano/aislamiento & purificación , Metapneumovirus/aislamiento & purificación , Rhinovirus/aislamiento & purificación , Adolescente , Adulto , Anciano , Brasil , Colesteatoma/patología , Estudios Transversales , Enterovirus/genética , Femenino , Bocavirus Humano/genética , Humanos , Masculino , Metapneumovirus/genética , Persona de Mediana Edad , Reacción en Cadena en Tiempo Real de la Polimerasa , Rhinovirus/genética , Adulto JovenRESUMEN
BACKGROUND: To provide basic demographic information and clinicopathologic features of ophthalmic Rosai-Dorfman disease (RDD) with a literature review. METHODS: A multi-centre retrospective case series reviewing all patients with histopathologically confirmed ophthalmic RDD at three tertiary eye care centres between January 1993 and December 2018. RESULTS: Eleven eyes of eight patients with histopathologically confirmed ophthalmic RDD were included, with equal numbers of males and females. The median age was 40.25 years (range: 26.6-72.4). Two patients had familial RDD. The orbit was the most commonly involved site (90.9% eyes). One patient (one eye) presented with a scleral nodule, anterior uveitis and cystoid macular oedema. Visual acuity ranged from 20/25 to light perception. Six patients had an extra-nodal ophthalmic disease, and the remaining two had an associated submandibular lymphadenopathy (nodal RDD). CONCLUSIONS: Ophthalmic RDD can be the only manifestation of this systemic disease, with the orbit being the most commonly involved site, exhibiting bone destruction, intracranial and/or sinus involvement and variable degree of visual loss. Ophthalmic familial RDD represent a severe form with a malignant course. Steroid monotherapy may be inadequate to control orbital RDD; thus, combined treatment is usually necessary. A comprehensive approach to assessment and management is recommended.
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Histiocitosis Sinusal , Edema Macular , Adulto , Femenino , Histiocitosis Sinusal/diagnóstico , Humanos , Masculino , Estudios Retrospectivos , Trastornos de la Visión , Agudeza VisualRESUMEN
Congenital optic nerve cystic-like malformations associated with normally developed globes are extremely rare. We describe 3 children who presented since birth with proptosis, and eye motility limitation. MRI showed in all cases that the intraorbital segment of the optic nerves was malformed with large cystic-like lesions in the intraconal segment of the orbit. In all cases, biopsies of the wall of the lesions were positive for glial fibrillary acidic protein. Since this protein is a neurobiomarker that exists only in astrocytes in the central nervous system, nonmyelinating Schwann cells of peripheral nerves, and enteric glial cells, we believe that these lesions represent true opticmeningoceles.
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Exoftalmia , Meningocele/diagnóstico , Nervio Óptico/patología , Astrocitos , Niño , Proteína Ácida Fibrilar de la Glía , Humanos , Neuroglía , Células de SchwannRESUMEN
The association of C-antineutrophil cytoplasmic antibody (ANCA) vasculitis and IgG4 positivity is a new condition not well described in clinical terms. The authors examined a 28-year-old man with a previous diagnosis of eosinophilic granulomatosis with polyangiitis, formerly known as Churg-Strauss disease, who presented with bilateral orbital inflammation. Magnetic resonance imaging revealed diffuse orbital infiltration and enlargement of the major divisions of the trigeminal nerve. Biopsy of the orbital contents showed necrotizing granulomatous vasculitis and a high number of IgG4-positive plasma cells (IgG4/IgG = 60%).
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Síndrome de Churg-Strauss , Granulomatosis con Poliangitis , Adulto , Anticuerpos Anticitoplasma de Neutrófilos , Síndrome de Churg-Strauss/complicaciones , Síndrome de Churg-Strauss/diagnóstico , Granulomatosis con Poliangitis/complicaciones , Granulomatosis con Poliangitis/diagnóstico , Humanos , Inmunoglobulina G , Masculino , Células PlasmáticasRESUMEN
PURPOSE: To describe the occurrence of multiple trigeminal nerves (TGNs) enlargement in patients with orbital IgG4-related disease. METHODS: Retrospective review of MRI findings and medical records of 6 patients (10 orbits) with orbital IgG4-related disease and enlargement of more than 1 TGN. Orbital biopsies were performed in all cases revealing the typical lymphoplasmacytic infiltrate with significant plasma cell positivity for IgG4 (IgG4+/IgG ratio ≥ 40%). Three experienced neuroradiologists reviewed the MRI sequences using a digital imaging viewer system (Horos, https://horosproject.org/). RESULTS: Bilateral involvement of at least 2 TGNs divisions was detected in all 6 patients. Enlargement of both V1 and V2 nerves was diagnosed in 5 patients, and in 3 cases, all TGN divisions were involved. V2 nerves were the most affected. In this division, all 12 infraorbital nerves were enlarged, followed by lesser palatines (10/83.3%), superior alveolar (10/83.3%), and zygomatic (6/50%). V1 and V3 nerves were less affected albeit 9 (75%) frontal branches (V1), and 50% of the inferior alveolar (V3) nerves were also enlarged. CONCLUSIONS: Widespread involvement of the TGN is an important feature of IgG4-related disease.
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Enfermedad Relacionada con Inmunoglobulina G4 , Enfermedades Orbitales , Humanos , Inmunoglobulina G , Enfermedades Orbitales/diagnóstico , Estudios Retrospectivos , Nervio TrigéminoRESUMEN
Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasia commonly affecting children with frequent somatic mutations in MAPK pathway genes including BRAFV600E and MAP2K1. Some studies suggest that LCH cells can recruit and modulate inflammatory cells, which could provide reciprocal survival signals. To characterize the immune profile of infiltrating inflammatory cells, and to clarify their participation in LCH pathogenesis, a detailed immunohistochemical analysis was performed. Fifteen (10 children, 5 adults) LCH cases were assessed through macrophage (CD68 and CD163), mature dendritic cell (mDC; CD83 and CD208), regulatory T cell (Treg; CD4, CD25 and FOXP3) and cytotoxic lymphocyte (CL; CD56, CD57, perforin and granzyme B) immunomarkers. Moreover, lymphocytic and LCH markers were also analysed. All cases were S100, CD1a, CD207 and CD4-positive. Bcl-2 and cyclin D1 expression was observed in 13 of 15 cases. In the immune microenvironment, M2-polarized macrophages and Tregs were the predominant cell populations, followed by significantly (P < .005) smaller levels of mDCs and CLs. Additionally, the number of CD3 + cells was significantly higher than that of CD20 + cells. In the CD3 + cell population, there were a significantly higher number of CD4 + cells than CD8 + cells. While there were no differences when comparing the paediatric and adult populations, FOXP3 + cells were significantly higher in patients with multisystem involvement and treated with chemotherapy, than single-site cases and those without chemotherapy. Our results suggest that M2-polarized macrophages and Treg infiltration can promote LCH development and survival, probably through pro-tumoral, immunosuppressive and/or cytokine-mediated mechanisms. This work highlights the need for further exploration of immune-targeted therapy for LCH.
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Histiocitosis de Células de Langerhans/metabolismo , Células de Langerhans/fisiología , Macrófagos/metabolismo , Linfocitos T Reguladores/metabolismo , Adulto , Antígenos CD/metabolismo , Diferenciación Celular , Microambiente Celular , Niño , Preescolar , Citocinas/metabolismo , Células Dendríticas/metabolismo , Femenino , Factores de Transcripción Forkhead/metabolismo , Humanos , Inmunohistoquímica/métodos , Lactante , Macrófagos/inmunología , Masculino , Linfocitos T Citotóxicos/metabolismo , Linfocitos T Reguladores/inmunología , Células Th2/inmunologíaRESUMEN
BACKGROUND: Acquired angioedema due to C1 inhibitor deficiency (AAE-C1-INH) is a very rare disease. In clinical practice, it may be difficult to differentiate AAE-C1-INH from hereditary angioedema due to C1-INH deficiency (HAE-C1-INH). In both conditions, patients are at an increased risk of death from asphyxiation due to upper airway obstruction. The association of AAE-C1-INH with lymphoproliferative and autoimmune diseases, and with presence of anti-C1-INH antibodies has been well documented, and treatment of the underlying condition may result in complete remission of angioedema. OBJECTIVES: To discuss the clinical evaluation, diagnosis, and treatment outcomes of AAE-C1-INH in the context of the care of 2 patients with recurrent isolated angioedema. METHODS: Two patients were followed up prospectively at our clinic. Measurements of C3, C4, C1-INH, and C1q levels were carried out by nephelometry, and the functional activity of C1-INH was determined by a chromogenic assay. Hematological investigation included morphological and immunophenotyping analysis of peripheral blood, bone marrow, and spleen histopathology. Sequencing of the 8 exons and adjacent intronic regions of the SERPING1 gene was performed using the Sanger method. RESULTS: Two patients were diagnosed with AAE-C1-INH associated with splenic marginal zone lymphoma during follow-up. CONCLUSIONS: Close follow-up, including detailed clinical history, physical examination, and laboratory tests, of our patients with AAE-C1-INH was essential for the early diagnosis and successful treatment of the lymphoproliferative disease, leading to the resolution of the angioedema attacks.
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Angioedema/diagnóstico , Angioedemas Hereditarios/diagnóstico , Linfoma de Células B de la Zona Marginal/diagnóstico , Bazo/patología , Neoplasias del Bazo/diagnóstico , Angioedema/terapia , Angioedemas Hereditarios/terapia , Detección Precoz del Cáncer , Servicios Médicos de Urgencia , Epinefrina/uso terapéutico , Femenino , Humanos , Linfoma de Células B de la Zona Marginal/terapia , Persona de Mediana Edad , Nefelometría y Turbidimetría , Neoplasias del Bazo/terapiaRESUMEN
OBJECTIVE: To report the frequency of Lynch syndrome (LS) in a cohort of patients from Southeast Brazil bearing endometrial cancer (EC), using a tumor screening universal approach. METHODS: A total of 242 endometrial carcinomas were screened by immunohistochemistry (IHC) and microsatellite instability (MSI) for detection of DNA mismatch repair deficiency (dMMR). MLH1 methylation was assessed to identify sporadic cases. Patients with dMMR tumors were recruited for germline variant analysis by next-generation sequencing of the MLH1, MSH2, MSH6, PMS2, and EPCAM genes. RESULTS: Ninety-three out of 242 tumors (38.5%) were classified as dMMR based on MSI and IHC results. Of these, 54 cases were selected for germline analysis, and 37/54 (68.5%) were available for sequencing. Ten patients (10/37, 27%) harbored germline pathogenic or likely pathogenic variants, most of them in the MSH6 gene (4/10, 40%). Seven variants of uncertain significance were found. Eight novel germline variants were identified. The LS prevalence in our cohort was of at least 4.1%. LS patients presented lower mean age at cancer diagnosis compared with patients diagnosed with sporadic EC. Individuals with dMMR tumors, without germline pathogenic variants detected in LS-genes ("Lynch-like" syndrome), had an intermediate mean age at cancer diagnosis between LS and sporadic cases. CONCLUSION: This is the first report of the LS prevalence in EC screened by a universal approach in Brazil. Our findings contribute to a better understanding of the mutational landscape of this syndrome in Brazil, which is relevant for improved identification, genetic counseling, prevention and control of cancer in LS.
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Biomarcadores de Tumor/genética , Neoplasias Colorrectales Hereditarias sin Poliposis/epidemiología , Detección Precoz del Cáncer/estadística & datos numéricos , Neoplasias Endometriales/genética , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/análisis , Brasil/epidemiología , Neoplasias Colorrectales Hereditarias sin Poliposis/complicaciones , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Neoplasias Colorrectales Hereditarias sin Poliposis/prevención & control , Metilación de ADN , Reparación de la Incompatibilidad de ADN , Análisis Mutacional de ADN , Neoplasias Endometriales/diagnóstico , Neoplasias Endometriales/patología , Neoplasias Endometriales/prevención & control , Endometrio/patología , Femenino , Asesoramiento Genético/organización & administración , Asesoramiento Genético/estadística & datos numéricos , Mutación de Línea Germinal , Heterocigoto , Humanos , Inmunohistoquímica , Inestabilidad de Microsatélites , Persona de Mediana Edad , Prevalencia , Estudios Prospectivos , Estudios RetrospectivosRESUMEN
Endometrial cancer (EC) harboring heterozygous POLE proofreading inactivating mutations (POLE-exo*) is associated with an increased number of somatic mutations that result in a distinctive anti-tumor immune response. However, the consequences of such POLE mutations in the context of the missing wild-type allele have not yet been described in endometrial tumors. A 72-year-old woman harboring a germline monoallelic frameshift mutation (p.Pro269fsTer26) in POLE was diagnosed with an EC having a somatic heterozygous mutation in the exonuclease domain of POLE (S459F). Targeted gene sequencing revealed an ultramutated phenotype (381 mutations/Mb) in the tumor and a 2-fold excess of mutations on the DNA leading strand. Additionally, we observed a mutational signature similar to the COSMIC signature 10, a higher mutation rate in this tumor than in endometrial tumors with heterozygous POLE-exo*, and an increased number of T lymphocytes. This is the first report of an ultramutated EC harboring a somatic POLE-exo* mutation in association with a germline loss-of-function mutation in this gene. The absence of a wild type POLE allele led to a particularly high mutational burden.