RESUMO
von Hippel-Lindau (VHL) disease is characterized by biallelic inactivation of the VHL gene leading to abnormal or absent VHL protein function, and constitutive activation of hypoxia-inducible factors (HIF) that leads to pro-tumorigenic signaling. Individuals with VHL disease develop numerous cysts and tumors involving multiple organs including the kidneys, central nervous system, endolymphatic sac, lungs, pancreatobiliary system, adrenal glands, epididymis, and/or broad ligament. On histologic examination, these lesions show morphologic overlap as they are frequently characterized by cells with clear cytoplasm and prominent vascularity. In addition to distinguishing non-renal tumors from metastatic clear cell renal cell carcinoma, understanding site-specific histopathologic and immunophenotypic features of these tumors has several applications. This includes distinguishing VHL-related tumors from those that arise sporadically and lack VHL gene alterations, guiding further genetic workup, and helping distinguish between different genetic predisposition syndromes. In this context, immunohistochemical studies for markers such as paired box 8 (PAX-8), carbonic anhydrase 9 (CA9), and glucose transporter 1 (GLUT-1) have an important role in routine clinical practice and represent cost-effective diagnostic tools. The recent development of targeted therapeutics directed against HIF-mediated signaling represents a significant milestone in the management of VHL disease and highlights the importance of accurately diagnosing and characterizing the wide spectrum of VHL disease-associated lesions.
Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Doença de von Hippel-Lindau , Masculino , Feminino , Humanos , Doença de von Hippel-Lindau/complicações , Doença de von Hippel-Lindau/diagnóstico , Doença de von Hippel-Lindau/genética , Proteína Supressora de Tumor Von Hippel-Lindau/genética , Proteína Supressora de Tumor Von Hippel-Lindau/metabolismo , Carcinoma de Células Renais/diagnóstico , Carcinoma de Células Renais/genética , Neoplasias Renais/diagnóstico , Neoplasias Renais/genética , Rim/patologiaRESUMO
INTRODUCTION: Enteral feeding prior to cardiac surgery has benefits in pre-operative and post-operative patient statuses. In 2020, to increase pre-operative feeding for single-ventricle patients prior to stage 1 palliation, an enteral feeding algorithm was created. The aim of this study is to monitor the impact of our practice change with the primary outcome of necrotising enterocolitis incidence from birth to 2 weeks following surgical intervention. METHODS: This is a single-site, retrospective cohort study including patients from 1 March, 2018 to 1 July, 2022. Variables assessed include demographics, age at cardiac surgery, primary cardiac diagnosis, necrotising enterocolitis pre-operative and 2 weeks post-operative cardiac surgery, feeding route, feeding type, volume of trophic enteral feeds, and near-infrared spectroscopy. RESULTS: Following implementation of a pre-operative enteral feeding algorithm, the rate of neonates fed prior to surgery increased (39.5-75%, p = .001). The feedings included a mean volume of 28.24 ± 11.16 ml/kg/day, 83% fed breastmilk only, 44.4% tube fed, and 55.5% of infants had all oral feedings. Comparing enterally fed neonates and those not enterally fed, the necrotising enterocolitis incidence from birth to 2 weeks post-op was not significantly increased (p = 0.926). CONCLUSION: As a result of implementing our feeding algorithm, the frequency of infants fed prior to stage I Norwood or Hybrid surgeries increased to 75%, and there was no significant change in the incidence of necrotising enterocolitis. This study confirmed that pre-operative enteral feeds are safe and are not associated with increased incidence of necrotising enterocolitis.
Assuntos
Enterocolite Necrosante , Doenças Fetais , Coração Univentricular , Lactente , Feminino , Recém-Nascido , Humanos , Nutrição Enteral/métodos , Estudos Retrospectivos , Enterocolite Necrosante/epidemiologia , Enterocolite Necrosante/etiologia , Coração Univentricular/complicaçõesRESUMO
INTRODUCTION: Adamantinoma-like Ewing sarcoma (ALES) is a rare aggressive malignancy occasionally diagnosed in the thyroid gland. ALES shows basaloid cytomorphology, expresses keratins, p63, p40, frequently CD99, and harbours the t(11;22) EWSR1::FLI1 translocation. There is debate on whether ALES resembles more sarcoma or carcinoma. METHODS: We performed RNA sequencing from two ALES cases and compared findings with skeletal Ewing's sarcomas and nonneoplastic thyroid tissue. ALES was investigated by in situ hybridization (ISH) for high-risk human papillomavirus (HPV) DNA and immunohistochemistry for the following antigens: keratin 7, keratin 20, keratin 5, keratins (AE1/AE3 and CAM5.2), CD45, CD20, CD5, CD99, chromogranin, synaptophysin, calcitonin, thyroglobulin, PAX8, TTF1, S100, p40, p63, p16, NUT, desmin, ER, FLI1, INI1, and myogenin. RESULTS: An uncommon EWSR1::FLI transcript with retained EWSR1 exon 8 was detected in both ALES cases. Regulators of EWSR1::FLI1 splicing (HNRNPH1, SUPT6H, SF3B1) necessary for production of a functional fusion oncoprotein, as well as 53 genes (including TNNT1, NKX2.2) activated downstream to the EWSR1::FLI1 cascade, were overexpressed. Eighty-six genes were uniquely overexpressed in ALES, most of which were related to squamous differentiation. Immunohistochemically, ALES strongly expressed keratins 5, AE1/AE3 and CAM5.2, p63, p40, p16, and focally CD99. INI1 was retained. The remaining immunostains and HPV DNA ISH were negative. CONCLUSION: Comparative transcriptomic profiling reveals overlapping features of ALES with skeletal Ewing's sarcoma and an epithelial carcinoma, as evidenced by immunohistochemical expression of keratin 5, p63, p40, CD99, the transcriptome profile, and detection of EWSR1::FLI1 fusion transcript by RNA sequencing.
Assuntos
Adamantinoma , Carcinoma , Infecções por Papillomavirus , Sarcoma de Ewing , Humanos , Sarcoma de Ewing/diagnóstico , Sarcoma de Ewing/genética , Adamantinoma/diagnóstico , Adamantinoma/genética , Adamantinoma/química , Glândula Tireoide/patologia , Transcriptoma , Queratina-5/metabolismo , Proteína EWS de Ligação a RNA/genética , Proteína EWS de Ligação a RNA/metabolismo , Fatores de Transcrição/genética , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismoRESUMO
Psoriasiform dermatoses represent a wide array of skin diseases commonly encountered by clinicians and pathologists. While they may present a diagnostic challenge, thorough observation coupled with proper interpretation of subtle additional clinical or histopathologic features provide clues to the correct diagnosis. In this review, we provide updates on emerging entities and develop a systemic approach to establish the pathologic diagnosis, with emphasis on the importance of clinicopathologic correlation.
Assuntos
Psoríase , Diagnóstico Diferencial , Humanos , Patologistas , Psoríase/diagnóstico , Psoríase/patologiaRESUMO
A 34-year-old male presented with a swelling on the volar surface of the third digit of his right hand. This swelling was associated with pain and erythema. Ultrasound-guided needle biopsy was performed. Cytologic and histologic preparations together confirmed the diagnosis of a rarely encountered mixed epithelial and mesenchymal proliferation, an eccrine angiomatous hamartoma. To our knowledge, this case is the first to illustrate the cytomorphologic features of this rare lesion.
Assuntos
Hamartoma/patologia , Hemangioma/patologia , Doenças das Glândulas Sudoríparas/patologia , Adulto , Citodiagnóstico/métodos , Técnicas Citológicas , Hamartoma/diagnóstico , Hemangioma/diagnóstico , Humanos , Masculino , Doenças das Glândulas Sudoríparas/diagnósticoRESUMO
AIMS: Recently, a novel isoform of anaplastic lymphoma kinase, with alternative transcription initiation (ALKATI ), has been described in melanoma and is susceptible to targeted ALK-inhibitor therapy. Clinical outcomes of patients with ALKATI mutated melanoma as well as correlation with immunohistochemical (IHC) methods have not yet been described. METHODS AND RESULTS: Clinicopathological characteristics were abstracted for 324 patients with metastatic melanoma (MM). IHC, fluorescence in-situ hybridisation and RNA-based digital molecular analysis assays were performed on archival tissue from 173 stage III and 192 stage IV tumours. ALKATI was identified in 12.7 and 4.8% stage III and IV tumours, respectively. Discrete presentations of the ALKATI are seen: isolated ALKATI (n = 20) and mixed ALKATI (combined ALKATI and ALKWT ; n = 7). Isolated ALKWT expression (n = 4) was seen with no ALK fusions. Stage III patients showed improved survival with ALKATI expression compared to those with ALKWT or no expression [5-year survival 80, 95% confidence interval (CI) = 57-100% versus 43%, 95% CI = 34-55%, P = 0.013]. Clinicopathological characteristics were not statistically significant. Strong diffuse cytoplasmic staining of ALK IHC (n = 12) has a sensitivity of 52.2%, specificity 100%, PPV of 100% and NPV of 92.5% of detecting isolated ALKATI . CONCLUSION: Presence of ALKATI is a good prognostic indicator in MM. ALK IHC and digital molecular analysis can be incorporated into MM evaluation to identify patients with ALKATI for targeted therapy.
Assuntos
Quinase do Linfoma Anaplásico/genética , Melanoma/genética , Neoplasias Cutâneas/genética , Adulto , Idoso , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Isoformas de Proteínas/genética , Estudos Retrospectivos , Melanoma Maligno CutâneoRESUMO
Melanomas of female genital tract are rare tumors with poor prognosis. While BRAF-V600E is the most common pathogenic mutation seen in cutaneous sun-exposed melanomas, mucosal and anogenital melanomas usually lack BRAF mutations and instead they harbor KIT alterations. The American Joint Committee on Cancer staging guideline (AJCC eighth edition) recommends using cutaneous melanoma guidelines for vulvar melanoma staging and does not provide any recommendations for vaginal melanoma staging. The aim of this study is to investigate the mutational status of invasive melanomas arising from different anatomic sites in lower female genital tract (vulvar hair-bearing skin, glabrous skin, vagina and urethra) in a group of 37 patients. Tumors were analyzed using a DNA targeted next-generation sequencing panel covering the 21 most common genes and mutation hotspots in melanomas. The most common genetic alterations in invasive melanomas of lower female genital tract are KIT (32%), TP53 (22%), and NF1 (19%). Overall 66% (21/32) of cases showed a pathogenic alteration in at least one of the MAPK pathway genes. No statistical significance seen between different primary tumor sites and the frequency of the oncogenic mutations, nor were any significant differences found by mutation status. Only one case of urethral melanoma showed a BRAF non-V600E mutation (D594G). Our results suggest a similar molecular pathogenesis and overall survival in melanomas arising from lower female genital tract, irrespective of their exact location in the urogenital area. Future classifications of melanoma should consider grouping vulvar melanomas with mucosal rather than cutaneous melanomas.
Assuntos
Análise Mutacional de DNA , Melanoma/genética , Neoplasias Uretrais/genética , Neoplasias Vaginais/genética , Neoplasias Vulvares/genética , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Melanoma/mortalidade , Pessoa de Meia-Idade , Taxa de Sobrevida , Neoplasias Uretrais/mortalidade , Neoplasias Vaginais/mortalidade , Neoplasias Vulvares/mortalidadeRESUMO
BACKGROUND: Despite the success of immune checkpoint and targeted therapy, many patients with melanoma ultimately require further treatment. The combination of carboplatin, paclitaxel, and bevacizumab (CPB) has demonstrated promising activity in a single-arm study. In the current study, the authors performed a randomized phase 2 study to confirm efficacy and to determine whether adding everolimus would increase the activity of the combination. METHODS: Through the North Central Cancer Treatment Group, a total of 149 patients with unresectable AJCC 6th edition stage IV melanoma were randomized from May 2010 to May 2014 to either CPB or CPB with everolimus (CPBE). The primary endpoint was progression-free survival (PFS), with secondary endpoints of overall survival (OS), response rate, and tolerability. RESULTS: The CPB and CPBE treatment arms were balanced with regard to age (median age: 59 years vs 58 years) and high lactate dehydrogenase (48% vs 51%), but were unbalanced with regard to sex (male sex: 72% vs 55%; P = .03). Overall, there was no difference noted with regard to PFS, with a median PFS of 5.6 months for CPB versus 5.1 months for CPBE (hazard ratio [HR], 1.14; 95% confidence interval [95% CI], 0.81-1.62 [P = .44]), or for OS, with a median OS of 14.5 months for CPB versus 10.8 months for CPBE (HR, 1.16; 95% CI, 0.84-1.84). The confirmed response rate was 13% for CPB and 23% for CPBE (P = .13). Toxicity was higher for CPBE compared with CPB (83% for grade 3 + and 14% for grade 4 + vs 63% for grade 3 + and 11% for grade 4+, respectively) (toxicities were graded using the Cancer Therapy Evaluation Program of the National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.0]). Common grade 3 + toxicities were neutropenia, leukopenia, and fatigue, which occurred in both treatment arms with comparable frequency. CONCLUSIONS: Both experimental arms demonstrated activity, with a PFS of >5 months. However, the addition of everolimus to CPB failed to improve outcomes, with increased toxicity noted. These findings replicate the moderate antitumor activity of CPB, with future development possibly in combination with targeted or immunotherapy. Cancer 2018;124:537-45. © 2017 American Cancer Society.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Melanoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bevacizumab/administração & dosagem , Carboplatina/administração & dosagem , Intervalo Livre de Doença , Everolimo/administração & dosagem , Feminino , Humanos , Masculino , Melanoma/genética , Melanoma/mortalidade , Melanoma/secundário , Pessoa de Meia-Idade , Mutação , Paclitaxel/administração & dosagem , Proteínas Proto-Oncogênicas B-raf/genéticaRESUMO
LESSONS LEARNED: Everolimus does not have sufficient activity to justify its use as single agent in metastatic melanoma.Patients treated with 10 mg per day dose were most likely to require dose reductions.Everolimus appeared to reduce the numbers of regulatory T cells in approximately half of the treated patients; unfortunately, these effects were not correlated with clinical outcomes. BACKGROUND: Everolimus (RAD-001) is an orally active rapamycin analogue shown in preclinical data to produce cytostatic cell inhibition, which may be potentially beneficial in treating melanoma. We conducted a phase II study to evaluate the efficacy and safety of everolimus in patients with unresectable metastatic melanoma (MM). METHODS: This study included two cohorts; cohort 1 received 30 mg of everolimus by mouth (PO) weekly, and cohort 2 was dosed with 10 mg of everolimus PO daily. The endpoints of the study were safety, 16-week progression-free survival (PFS), overall survival (OS), and measures of immunomodulatory/antiangiogenic properties with therapy. Tumor samples before therapy and at week 8 of treatment were analyzed. Peripheral blood plasma or mononuclear cell isolates collected prior to therapy and at weeks 8 and 16 and at time of tumor progression were analyzed for vascular endothelial growth factor and regulatory T-cell (Treg) measurements. RESULTS: A total of 53 patients were enrolled in cohort 1 (n = 24) and cohort 2 (n = 29). Only 2 patients of the first 20 patients enrolled in cohort 2 had treatment responses (25%; 95% confidence interval, 8.6%-49.1%); this result did not allow full accrual to cohort 2, as the study was terminated for futility. Median OS was 12.2 months for cohort 1 versus 8.1 months in cohort 2; no PFS advantage was seen in either group (2.1 months vs. 1.8 months). Dose-limiting toxicities included grade 4 myocardial ischemia (3.4%); grade 3 fatigue, mucositis, and hyperglycemia (10.3%); and anorexia and anemia (6.9%). Everolimus significantly reduced the number of Tregs in approximately half of the treated patients; however, these effects were not correlated with clinical outcomes. CONCLUSION: Everolimus does not have sufficient single-agent activity in MM; however, we have identified evidence of biological activity to provide a potential rationale for future combination studies.
Assuntos
Antineoplásicos/uso terapêutico , Everolimo/uso terapêutico , Melanoma/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/farmacologia , Everolimo/farmacologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Adulto JovemRESUMO
Adrenocortical carcinomas are rare tumours that can be diagnostically challenging. Numerous multiparametric scoring systems and diagnostic algorithms have been proposed to differentiate adrenocortical adenoma from adrenocortical carcinoma. Adrenocortical neoplasms must also be differentiated from other primary adrenal tumours, such as phaeochromocytoma and unusual primary adrenal tumours, as well as metastases to the adrenal gland. Myxoid, oncocytic and sarcomatoid variants of adrenocortical tumours must be recognized so that they are not confused with other tumours. The diagnostic criteria for oncocytic adrenocortical carcinoma are different from those for conventional adrenocortical carcinomas. Adrenocortical neoplasms in children are particularly challenging to diagnose, as histological features of malignancy in adrenocortical neoplasms in adults may not be associated with aggressive disease in the tumours of children. Recent histological and immunohistochemical studies and more comprehensive and integrated genomic characterizations continue to advance our understanding of the tumorigenesis of these aggressive neoplasms, and may provide additional diagnostic and prognostic utility and guide the development of therapeutic targets.
Assuntos
Neoplasias do Córtex Suprarrenal/diagnóstico , Adenoma Adrenocortical/diagnóstico , Carcinoma Adrenocortical/diagnóstico , Neoplasias do Córtex Suprarrenal/patologia , Adenoma Adrenocortical/patologia , Carcinoma Adrenocortical/patologia , Adulto , Criança , Diagnóstico Diferencial , Humanos , Patologia CirúrgicaRESUMO
Papillary thyroid carcinomas are the most common endocrine cancer and are usually associated with good survival. However, some variants of papillary thyroid carcinomas may behave more aggressively than classic papillary thyroid carcinomas. The tall cell variant of papillary thyroid carcinoma is the most common aggressive variant of papillary thyroid carcinoma. The aggressive behavior has been ascribed to the histologic subtype and/or to the clinicopathologic features, an issue that remains controversial. The columnar variant of papillary thyroid carcinoma can be aggressive, particularly in older patients, with larger tumors showing a diffusely infiltrative growth pattern and extrathyroidal extension. A papillary thyroid carcinoma is designated as solid/trabecular variant when all or nearly all of a tumor not belonging to any of the other variants has a solid, trabecular, or nested (insular) appearance. This tumor must be distinguished from poorly differentiated thyroid carcinoma which has the same growth pattern but lacks nuclear features of papillary thyroid carcinoma and may show tumor necrosis and high mitotic activity. New to the fourth edition of the WHO Classification of Tumours of Endocrine Organs, the hobnail variant of papillary thyroid carcinoma is a moderately differentiated papillary thyroid carcinoma variant with aggressive clinical behavior and significant mortality. All of these variants are histologically unique and important to recognize due to their aggressive behavior.
Assuntos
Carcinoma Papilar/patologia , Neoplasias da Glândula Tireoide/patologia , Adulto , Idoso , Carcinoma Papilar/classificação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Câncer Papilífero da Tireoide , Neoplasias da Glândula Tireoide/classificaçãoRESUMO
LESSONS LEARNED: Percutaneous thermal ablation combined with in situ granulocyte-macrophage colony-stimulating factor cytokine therapy was technically feasible and well tolerated.No significant clinical or immunologic responses were seen. BACKGROUND: Melanoma tumor-derived heat-shock proteins (HSPs) and HSP-peptide complexes can elicit protective antitumor responses. The granulocyte-macrophage colony-stimulating factor (GM-CSF) chemokine can also promote uptake and processing by professional antigen presenting cells (APCs). On this basis, we designed a pilot study of percutaneous thermal ablation as a means to induce heat-shock protein vaccination plus GM-CSF to determine safety and preliminary antitumor activity of this combination. MATERIALS AND METHODS: This study was designed to assess overall safety of percutaneous ablation combined with GM-CSF for unresectable, metastatic melanoma including uveal and mucosal types. All patients received heat-shock therapy (42°C for 30 minutes), then received one of three treatments: (a) intralesional GM-CSF (500 mcg standard dose); (b) radiofrequency ablation (RFA) + GM-CSF; or (c) cryoablation plus GM-CSF. The primary endpoint of the study was the induction of endogenous HSP70 and melanoma-specific cytotoxic T lymphocytes (CTL). RESULTS: Nine patients (three per study arm) were enrolled. No dose-limiting toxicity was observed as specified per protocol. All patients developed progressive disease and went on to receive alternative therapy. Median overall survival (OS) was 8.2 months (95% confidence interval [CI] 2-17.2). The study was not powered to detect a difference in clinical outcome among treatment groups. CONCLUSION: Percutaneous thermal ablation plus GM-CSF was well tolerated, technically feasible, and demonstrated an acceptable adverse event profile comparable to conventional RFA and cryoablation. While HSP70 was induced following therapy, the degree of HSP70 elevation was not associated with clinical outcome or induced CTL responses. While percutaneous thermal ablation plus GM-CSF combinations including checkpoint inhibitors could be considered in future studies, the use of GM-CSF remains experimental and for use in the context of clinical trials.
Assuntos
Criocirurgia/efeitos adversos , Fator Estimulador de Colônias de Granulócitos e Macrófagos/uso terapêutico , Hipertermia Induzida/efeitos adversos , Imunoterapia/efeitos adversos , Melanoma/terapia , Neoplasias Cutâneas/terapia , Idoso , Idoso de 80 Anos ou mais , Terapia Combinada , Criocirurgia/métodos , Estudos de Viabilidade , Feminino , Proteínas de Choque Térmico HSP70/metabolismo , Humanos , Hipertermia Induzida/métodos , Imunoterapia/métodos , Injeções Intralesionais , Estimativa de Kaplan-Meier , Masculino , Melanoma/imunologia , Melanoma/mortalidade , Melanoma/patologia , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Projetos Piloto , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/patologia , Linfócitos T Citotóxicos/efeitos dos fármacos , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/efeitos da radiação , Resultado do TratamentoRESUMO
Adrenocortical carcinoma is a rare endocrine tumor with a poor prognosis. These tumors can be diagnostically challenging, and diagnostic algorithms and criteria continue to be suggested. Myxoid and oncocytic variants are important to recognize to not confuse with other tumors. In addition, the diagnostic criteria are different for oncocytic adrenal carcinomas than conventional carcinomas. Adrenocortical carcinomas usually occur in adults, but can also occur in children. In children these tumors are diagnostically challenging as the histologic features of malignancy seen in an adult tumor may not be associated with aggressive disease in a child. Adrenocortical carcinomas occur with increased frequency in Beckwith-Wiedemann and Li-Fraumeni syndromes, but most occur sporadically. Gene expression profiling by transcriptome analysis can discriminate adrenocortical carcinomas from adenomas and divide carcinomas into prognostic groups. The increasing understanding of the pathogenesis of these tumors may provide increasing treatment targets for this aggressive tumor.
Assuntos
Neoplasias do Córtex Suprarrenal , Carcinoma Adrenocortical , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias do Córtex Suprarrenal/genética , Neoplasias do Córtex Suprarrenal/metabolismo , Neoplasias do Córtex Suprarrenal/patologia , Carcinoma Adrenocortical/genética , Carcinoma Adrenocortical/metabolismo , Carcinoma Adrenocortical/patologia , Humanos , Gradação de Tumores , PrognósticoRESUMO
Critical illness-related corticosteroid insufficiency (CIRCI) can cause hemodynamic instability in neonates after congenital heart surgery with manifestations that increase morbidity and potential mortality. We retrospectively reviewed neonates who underwent cardiac surgery between August 2018 and July 2020 at a freestanding children's hospital, had next-generation sequencing performed, and had their cortisol levels drawn as standard clinical care after cardiac surgery. The groups were defined as CIRCI (with a cortisol level ≤ 4.5 mcg/dL) and non-CIRCI (level > 4.5 mcg/dL). The CIRCI group (n = 8) had a 100% incidence of heterozygous gene mutation on STX1A with splicing or loss of function, and this mutation was not found in the non-CIRCI group (n = 8). Additional gene mutations were found in the CIRCI group on RAB6A, ABCA3, SIDT2, and LILRB3, with no incidence in the non-CIRCI group. Three additional mutations were found across the CIRCI group in INPPL1 and FAM189A2 (both splicing and missense), with 12-25% of patients in the non-CIRCI group also displaying these mutations. Novel genetic abnormalities were seen in neonates with symptoms of CIRCI with potential cardiac implications from a gene mutation for STX1A. Compounding effects of additional gene mutations need to be confirmed and explored for potential predisposition to hemodynamic instability during times of stress.
Assuntos
Insuficiência Adrenal , Procedimentos Cirúrgicos Cardíacos , Insuficiência Cardíaca , Proteínas de Transporte de Nucleotídeos , Criança , Recém-Nascido , Humanos , Hidrocortisona , Insuficiência Adrenal/diagnóstico , Insuficiência Adrenal/etiologia , Estudos Retrospectivos , Estado Terminal/epidemiologia , Corticosteroides , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Insuficiência Cardíaca/complicações , Receptores Imunológicos , Antígenos CDRESUMO
OBJECTIVES: There is a paucity of data on North American cohorts of patients with penile squamous cell carcinoma (pSCC). Herein, we aimed to assess the sensitivity of various modalities to identify human papillomavirus (HPV) status, determine the prevalence of high-risk HPV-positivity, and evaluate the prognostic impact of relevant clinicopathologic variables. METHODS: Patients with pSCC (n = 121) consecutively treated with partial/total penectomy (2000-2022) at a single institution were included. HPV status (based on immunohistochemistry [IHC], in situ hybridization [ISH], and panviral metagenomic sequencing [PMS]), histologic features, and outcomes were reviewed. Outcome events included death due to disease and progression. RESULTS: The majority of patients were white (105/121, 86.8%). Thirty-seven (30.6%) were high-risk HPV-positive, and morphologic evaluation had a sensitivity of 97.3% (95% confidence interval [CI], 86.2-99.5) for predicting high-risk HPV status compared to IHC/ISH/PMS. Disease progression was more common among high-risk HPV-negative compared to high-risk HPV-positive patients (HR 2.74, CI 1.12-8.23, P = 0.03). Moreover, among high-risk HPV-negative patients, those with moderate-poorly differentiated tumors had increased disease-specific mortality (32.6%, CI 17.1-48.1) compared to those with well-differentiated tumors (0%). Among high-risk HPV-positive patients, those with basaloid morphology had lower disease-specific mortality (0% vs 14.4%, CI 0.0-33.1). CONCLUSIONS: We demonstrate high-risk HPV-positivity in approximately one-third of patients with pSCC. Morphologic evaluation alone had a high sensitivity in correctly determining HPV status. Our results suggest that high-risk HPV status and morphologic features (differentiation in high-risk HPV-negative, and basaloid subtype in high-risk HPV-positive pSCC) may have prognostic value.
Assuntos
Carcinoma de Células Escamosas , Infecções por Papillomavirus , Neoplasias Penianas , Humanos , Masculino , Neoplasias Penianas/virologia , Neoplasias Penianas/patologia , Neoplasias Penianas/mortalidade , Pessoa de Meia-Idade , Infecções por Papillomavirus/virologia , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/patologia , Carcinoma de Células Escamosas/virologia , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/mortalidade , Idoso , Imuno-Histoquímica , Adulto , Hibridização In Situ , Papillomaviridae/isolamento & purificação , Papillomaviridae/genética , Estudos Retrospectivos , Idoso de 80 Anos ou mais , Fatores de Risco , Prognóstico , Progressão da Doença , Valor Preditivo dos Testes , Papillomavirus HumanoRESUMO
The staging for pT2/pT3 penile squamous cell carcinoma (pSCC) has undergone major changes. Some authors proposed criteria wherein the distinction between pT2/pT3 was made using the same histopathological variables that are currently utilized to differentiate pT1a/pT1b. In this single-institution, North American study, we focused on (HPV-negative) pT2/3 pSCCs (i.e., tumors invading corpus spongiosum/corpus cavernosum), and compared the prognostic ability of the following systems: (i) AJCC (8th edition) criteria; (ii) modified staging criteria proposed by Sali et al. (Am J Surg Pathol. 2020; 44:1112-7). In the proposed system, pT2 tumors were defined as those devoid of lymphovascular invasion (LVI) or perineural invasion (PNI), and were not poorly differentiated; whereas pT3 showed one or more of the following: LVI, PNI, and/or grade 3. 48 pT2/pT3 cases were included (AJCC, pT2: 27 and pT3: 21; Proposed, pT2: 22 and pT3: 26). The disease-free survival (DFS) and progression-free survival (PFS) did not differ between pT2 and pT3, following the current AJCC definitions (p = 0.19 and p = 0.10, respectively). When the pT2/3 stages were reconstructed using the modified criteria, however, a statistically significant difference was present in both DFS and PFS between pT2 and pT3 (p = 0.004 and p = 0.003, respectively). The proposed staging system has the potential to improve the prognostication of pT2/pT3 tumors in pSCC. Each of these histopathologic variables has been shown to have a significant association with outcomes in pSCC, which is an advantage. Further studies are needed to demonstrate the utility of this modified staging system in patient populations from other geographic regions.
Assuntos
Carcinoma de Células Escamosas , Estadiamento de Neoplasias , Neoplasias Penianas , Humanos , Neoplasias Penianas/patologia , Neoplasias Penianas/virologia , Masculino , Estadiamento de Neoplasias/métodos , Estadiamento de Neoplasias/normas , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/virologia , Pessoa de Meia-Idade , Idoso , Adulto , Prognóstico , América do Norte , Idoso de 80 Anos ou maisRESUMO
There is increasing recognition of the high prevalence of hereditary predisposition syndromes in patients diagnosed with paraganglioma/pheochromocytoma. It is widely acknowledged that germline pathogenic alterations of the succinate dehydrogenase complex genes (SDHA, SDHB, SDHC, SDHD, SDHAF2) contribute to the pathogenesis of most of these tumors. Herein, we have provided an update on the biology and diagnosis of succinate dehydrogenase-deficient paraganglioma/pheochromocytoma, including the molecular biology of the succinate dehydrogenase complex, mechanisms and consequences of inactivation of this complex, the prevalence of pathogenic alterations, and patterns of inheritance.
Assuntos
Neoplasias das Glândulas Suprarrenais , Paraganglioma , Feocromocitoma , Humanos , Succinato Desidrogenase/genética , Feocromocitoma/diagnóstico , Feocromocitoma/genética , Prognóstico , Paraganglioma/diagnóstico , Paraganglioma/genética , Mutação/genética , Neoplasias das Glândulas Suprarrenais/diagnóstico , Neoplasias das Glândulas Suprarrenais/genética , Mutação em Linhagem Germinativa/genéticaRESUMO
This special issue of Human Pathology, highlighting updates in dermatopathology, represents a carefully curated collection of articles written by authors invited for their respective areas of expertise. This issue covers a range of important topics in neoplastic, inflammatory, or special-site dermatopathology, with an emphasis on "high-stakes" or emerging diagnoses or those that would be otherwise encountered infrequently by most practicing pathologists. In addition, topics important in clinical practice, including considerations relating to skin of color and cognitive bias in dermatopathology, are addressed. Throughout this issue, authors have incorporated scientific advances and recent literature to help pathologists tackle these difficult areas in dermatopathology.
RESUMO
Endocrine pathology comprises a spectrum of disorders originating in various sites throughout the body. Some disorders affect endocrine glands, and others arise from endocrine cells that are dispersed in non-endocrine tissues. Endocrine cells can broadly be classified as neuroendocrine, steroidogenic, or thyroid follicular cells; these three families have distinct embryologic origins, morphologic structure, and biochemical hormone synthetic pathways. Lesions affecting the endocrine system include developmental abnormalities, inflammatory processes that can be infectious or autoimmune, hypofunction with atrophy or hyperfunction caused by hyperplasia secondary to pathology in other sites, and neoplasia of many types. Understanding endocrine pathology requires knowledge of both structure and function, including the biochemical signaling pathways that regulate hormone synthesis and secretion. Molecular genetics has clarified sporadic and hereditary disease that is common in this field.
Assuntos
Sistema Endócrino , Hormônios , Humanos , HiperplasiaRESUMO
Primary hepatic neuroendocrine tumors and primary hepatic neuroendocrine carcinomas are rare and pose challenges for both diagnosis and for determining whether the tumor is primary to the liver versus metastatic disease. The lack of a uniform definition for primary hepatic neuroendocrine neoplasms is also a limitation to understanding and treating these rare tumors. Recently, there have been significant histological advances in the diagnosis and classification of neuroendocrine tumors in general, as well as significant advances in imaging for neuroendocrine neoplasms, all of which are important for their treatment. This article presents a multiple disciplinary definition and proposed guidelines for diagnosing a neuroendocrine tumor/neuroendocrine carcinomas as being primary to the liver.