RESUMO
CONTEXT: The lungs are a common site of tumor metastasis. While morphology and immunophenotype can help differentiate primary from metastatic tumors, distinguishing pulmonary invasive mucinous adenocarcinoma (PIMA) from metastatic colorectal adenocarcinoma (CRC) may occasionally be challenging due to overlapping morphological and immunohistochemical features. Lineage-specific markers such as CDX2, TTF-1, and napsin A are helpful with pulmonary non-mucinous adenocarcinoma (PNMA), however they are non-specific and insensitive when applied to PIMA. SATB2 is a newer marker that distinguishes CRC from upper gastrointestinal and pancreaticobiliary tumors; its utility in distinguishing CRC from PIMA has not been fully elucidated. OBJECTIVE: To evaluate the performance of lineage-specific and mucin glycoprotein immunostains in distinguishing PIMA and CRC. DESIGN: We stained tissue microarrays comprising 34 PNMA, 31 PIMA, and 32 CRC with CK7, CK20, SATB2, CDX2, villin, TTF-1, napsin A, and gel-forming mucins MUC2, MUC5AC, and MUC6. RESULTS: PIMA showed significant (>50% of cells) expression of SATB2 (6%), CDX2 (6%), villin (74%), TTF-1 (13%), and napsin A (23%). However, significant CK7 expression was seen in nearly all PIMA (30/31) and none of the metastatic CRC. CONCLUSION: Our results suggest that CK7 remains one of the most useful markers for distinguishing primary PIMA from metastatic CRC. Expression of the mucin glycoproteins MUC5AC and MUC6 and lack of expression of MUC2 favored a diagnosis of PIMA, but expression of these markers was too heterogeneous to be of clinical utility. To our knowledge this is the only study comparing the immunohistochemical profile of PIMA and metastatic CRC in lung metastasectomy specimens.
Assuntos
Adenocarcinoma Mucinoso , Biomarcadores Tumorais , Fator de Transcrição CDX2 , Neoplasias Colorretais , Imuno-Histoquímica , Neoplasias Pulmonares , Proteínas de Ligação à Região de Interação com a Matriz , Proteínas dos Microfilamentos , Mucina-2 , Mucina-6 , Fatores de Transcrição , Humanos , Neoplasias Colorretais/patologia , Proteínas de Ligação à Região de Interação com a Matriz/análise , Proteínas de Ligação à Região de Interação com a Matriz/metabolismo , Biomarcadores Tumorais/análise , Fator de Transcrição CDX2/análise , Fator de Transcrição CDX2/metabolismo , Neoplasias Pulmonares/secundário , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/diagnóstico , Adenocarcinoma Mucinoso/secundário , Adenocarcinoma Mucinoso/diagnóstico , Adenocarcinoma Mucinoso/patologia , Adenocarcinoma Mucinoso/metabolismo , Diagnóstico Diferencial , Fatores de Transcrição/análise , Mucina-6/análise , Proteínas dos Microfilamentos/análise , Mucina-2/análise , Mucina-5AC/análise , Análise Serial de Tecidos , Proteínas de Homeodomínio/análise , Mucinas/análise , Mucinas/metabolismoRESUMO
Validated nonbiopsy methods to assure duodenal mucosal healing in celiac disease are lacking, yet ongoing mucosal injury is associated with anemia, osteoporosis, and lymphoma. Most providers utilize clinical data as surrogates of mucosal status to avoid additional esophagogastroduodenoscopy. The reliability of such surrogates to predict mucosal recovery has been incompletely evaluated. The aim of this study was to rigorously assess patterns of histologic mucosal recovery at follow-up in celiac disease and to correlate findings with clinical data. Gastrointestinal pathologists from 13 centers evaluated initial and follow-up duodenal biopsies from 181 celiac disease patients. Marsh scores and intraepithelial lymphocytes (IELs)/100 enterocytes were assessed blindly. Histology at follow-up was correlated with symptoms, immunoglobulin A anti-tissue transglutaminase titers and gluten-free diet adherence. Fifty-six/181 (31%) patients had persistent villous blunting and 46/181 (25%) patients had just persistently elevated IELs at follow-up, with only 79/181 (44%) patients having complete histologic remission. IEL normalization (82/181; 45%) lagged villous recovery (125/181;69%). In a minority of patients, villous blunting was limited to proximal duodenal biopsies. No correlation was found between Marsh scores and symptoms, normalization of immunoglobulin A anti-tissue transglutaminase serology, or diet adherence. Children showed greater recovery of Marsh score ( P <0.001) and IELs ( P <0.01) than adults. Persistent mucosal injury is common in celiac disease, with discordant villous/IEL normalization. Pathologist awareness of expected findings in celiac disease follow-up biopsies, including their frequent lack of correlation with clinical data, is important for patient management, and has implications for eligibility criteria for therapeutics currently in development.
Assuntos
Doença Celíaca , Adulto , Criança , Humanos , Seguimentos , Reprodutibilidade dos Testes , Duodeno/patologia , Biópsia , Mucosa Intestinal/patologia , Imunoglobulina ARESUMO
Drug-induced liver injury (DILI) is a challenging and constantly changing field. The pathologist plays a key role in interpreting liver biopsies by classifying the pattern of injury, grading the severity of injury, and evaluating for other possible causes. Reports of iatrogenic liver injury are reviewed here with a focus on total parenteral nutrition (ie, intestinal failure-associated liver disease [IFALD]) and immune checkpoint inhibitors (ICIs). The hallmark features of IFALD are cholestasis and steatosis. Cholestasis is more common in infants, whereas steatosis and steatohepatitis are more commonly seen in older children and adults. Infants tend to have a faster progression to fibrosis and cirrhosis. Perivenular fibrosis and ductopenia may also be seen in IFALD. Although fish oil-based lipid emulsions can reverse cholestasis, recent studies have shown persistent or progressive fibrosis. ICI-induced liver injury usually presents as an acute hepatitis with features similar to those seen in idiopathic autoimmune hepatitis and drug-induced autoimmune hepatitis. However, it lacks a prominent plasma cell infiltrate and serological markers of autoimmune hepatitis. Other features such as fibrin ring granulomas and cholangitis have also been reported in association with ICIs. Treatment for ICI-induced liver injury includes corticosteroids and other immunosuppressants.
Assuntos
Antineoplásicos Imunológicos/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Colestase/etiologia , Fígado Gorduroso/etiologia , Doença Iatrogênica , Fígado/efeitos dos fármacos , Nutrição Parenteral Total/efeitos adversos , Biópsia , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Doença Hepática Induzida por Substâncias e Drogas/patologia , Colestase/tratamento farmacológico , Colestase/patologia , Fígado Gorduroso/tratamento farmacológico , Fígado Gorduroso/patologia , Humanos , Fígado/patologia , Valor Preditivo dos Testes , Prognóstico , Fatores de RiscoRESUMO
Acute hepatitis and acute liver failure are severe medical conditions that require early clinical intervention. Histopathologic findings on a liver biopsy or a liver explant may help identify the underlying etiology or provide an important direction for further clinical, laboratory and radiographical investigation. This review is divided into two main portions. The first portion concentrates on various etiologies and discusses unique histologic features that can be associated with specific etiologies. The second portion describes the general morphologic features based on which the diagnosis of acute hepatitis and acute liver failure are made. Histopathologic distinction between collapse and cirrhosis and limitations of histopathologic assessment for underlying etiologies are addressed in this portion. Another focus of this review is non-necrotic acute liver failure, which typically features diffuse microvesicular steatosis secondary to various etiologies causing mitochondrial dysfunction. Molecular testing serves an increasingly important role in the diagnosis and management of this group of disorders.
Assuntos
Hepatite/patologia , Falência Hepática Aguda/patologia , Doenças Mitocondriais/patologia , Doença Aguda , Biópsia , HumanosRESUMO
Goblet cell carcinoid (GCC) or goblet cell carcinoma is a unique mixed endocrine-exocrine neoplasm that is almost exclusively seen in the appendix. The hallmark of GCC is the concentric infiltration of the appendiceal wall by small tight clusters, nests or cords of tumor cells that exhibit a goblet cell morphology with a small compressed nucleus and conspicuous intracytoplasmic mucin. The coexistence of high-grade adenocarcinoma with GCC has been increasingly recognized as a common finding, which has been called adenocarcinoma ex GCC or mixed GCC-adenocarcinoma. A number of studies have shown that it is the high-grade adenocarcinomatous component that dictates the prognosis. Several histologic classification/grading systems have been proposed, which correlate with overall patient survival. Treatment options are primarily based on tumor stage and the presence or absence of a high-grade adenocarcinomatous component.
Assuntos
Adenocarcinoma/patologia , Neoplasias do Apêndice/patologia , Tumor Carcinoide/patologia , Células Caliciformes/patologia , Neoplasias Complexas Mistas/patologia , Adenocarcinoma/química , Adenocarcinoma/mortalidade , Adenocarcinoma/terapia , Neoplasias do Apêndice/química , Neoplasias do Apêndice/mortalidade , Neoplasias do Apêndice/terapia , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/genética , Biópsia , Tumor Carcinoide/química , Tumor Carcinoide/mortalidade , Tumor Carcinoide/terapia , Células Caliciformes/química , Humanos , Imuno-Histoquímica , Técnicas de Diagnóstico Molecular , Gradação de Tumores , Estadiamento de Neoplasias , Neoplasias Complexas Mistas/química , Neoplasias Complexas Mistas/mortalidade , Neoplasias Complexas Mistas/terapia , Resultado do TratamentoRESUMO
Nonimmune hydrops fetalis (NIHF) is a rare disorder with a high perinatal mortality of at least 50%. One cause of NIHF is generalized lymphatic dysplasia (GLD), a rare form of primary lymphedema of the extremities and systemic involvement including chylothoraces and pericardial effusions. An autosomal recessive form of GLD has been described, caused by variants in the PIEZO1 gene. It has been reported clinically to cause NIHF and childhood onset of facial and limb lymphedema, most of which were diagnosed postnatally. We present a case of a woman with recurrent pregnancies affected by NIHF because of novel compound heterozygous variants in the PIEZO1 gene diagnosed prenatally using exome sequencing (ES). Two variants in PIEZO1 (c.3206G>A and c.6208A>C) were identified that were inherited from the father and mother, and are predicted to cause a nonsense and missense change, respectively, in the PIEZO1 subunits. Ultrasound demonstrated severe bilateral pleural effusions, whole body edema and polyhydramnios. Histopathology revealed an increased number of lymphatic channels, many of which showed failure of luminal canalization. Sanger sequencing confirmed the same variants in a prior fetal demise. We provide phenotypic correlation with ultrasound and autopsy finding, review PIEZO1 variants as a cause of GLD and discuss the uses of prenatal ES to date.
Assuntos
Exoma , Variação Genética , Hidropisia Fetal/diagnóstico , Hidropisia Fetal/genética , Canais Iônicos/genética , Adulto , Autopsia , Biópsia , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Recém-Nascido , Gravidez , Ultrassonografia Pré-Natal , Sequenciamento do ExomaRESUMO
INTRODUCTION: Pseudoamniotic band syndrome (PABS) occurs iatrogenically after fetal surgery or amniocentesis due to chorioamniotic membrane separation. Separation of the amnion from the chorion can expand to form fibrous amniotic bands that can envelope fetal limbs or the umbilical cord, with consequences ranging from limb constriction to fetal demise. CASE REPORT: We report a case of bilateral fetal pleural effusions at 27 weeks' gestation treated by bilateral thoracoamniotic shunts. Following shunt placement, the hydrothorax resolved. However, chorioamniotic membrane separation developed resulting in PABS with subsequent umbilical cord strangulation and fetal demise at 32 weeks' gestation. CONCLUSION: PABS has been previously described in the literature following various fetal interventions. This is the first reported case of pseudoamniotic band syndrome after placement of fetal thoracoamniotic shunts. A high index of suspicion is required to diagnose PABS via postoperative ultrasound. Post intervention chorioamniotic membrane separation warrants close surveillance for sonographic evidence of PABS.
Assuntos
Síndrome de Bandas Amnióticas/etiologia , Quilotórax/congênito , Terapias Fetais/efeitos adversos , Hidropisia Fetal/cirurgia , Quilotórax/cirurgia , Feminino , Morte Fetal , Feto , Humanos , Derrame Pleural/cirurgia , GravidezRESUMO
The receptor tyrosine kinase AXL promotes migration, invasion, and metastasis. Here, we evaluated the role of AXL in endometrial cancer. High immunohistochemical expression of AXL was found in 76% (63/83) of advanced-stage, and 77% (82/107) of high-grade specimens and correlated with worse survival in uterine serous cancer patients. In vitro, genetic silencing of AXL inhibited migration and invasion but had no effect on proliferation of ARK1 endometrial cancer cells. AXL-deficient cells showed significantly decreased expression of phospho-AKT as well as uPA, MMP-1, MMP-2, MMP-3, and MMP-9. In a xenograft model of human uterine serous carcinoma with AXL-deficient ARK1 cells, there was significantly less tumor burden than xenografts with control ARK1 cells. Together, these findings underscore the therapeutic potentials of AXL as a candidate target for treatment of metastatic endometrial cancer.
Assuntos
Neoplasias do Endométrio/metabolismo , Neoplasias do Endométrio/patologia , Proteínas da Matriz Extracelular/metabolismo , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Receptores Proteína Tirosina Quinases/genética , Receptores Proteína Tirosina Quinases/metabolismo , Animais , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Neoplasias do Endométrio/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos , Gradação de Tumores , Invasividade Neoplásica , Transplante de Neoplasias , Fosforilação , Prognóstico , Transdução de Sinais , Análise de Sobrevida , Regulação para Cima , Receptor Tirosina Quinase AxlRESUMO
Leber hereditary optic neuropathy (LHON) is one of the most common inherited optic neuropathies causing bilateral central vision loss. The disorder results from point mutations in mitochondrial DNA and subsequent mitochondrial dysfunction. The primary cell type that is lost in LHON is the retinal ganglion cell, which is highly susceptible to disrupted ATP production and oxidative stress. Inheritance of LHON follows that of mitochondrial genetics, and it has a highly variable clinical phenotype, as other genetic and environmental factors also play a role. Although LHON usually presents with isolated vision loss, some patients suffer other neurological sequelae. For ill-defined reasons, male LHON mutation carriers are more affected than females. Most LHON patients remain legally blind, but a small proportion can experience spontaneous partial recovery, often within the first year of symptom onset. Unfortunately, at this time there are no established curative interventions and treatment is largely supportive. Patients should be offered low vision services and counseled on mitigating risk factors for additional vision loss, such as smoking and consuming alcohol. Encouraging treatments currently undergoing investigation includes ubiquinone analogs, such as idebenone, as well as gene therapy and stem cells to restore ATP synthesis and provide neuroprotection to surviving retinal ganglion cells.
RESUMO
Secondary bacterial pneumonias are a frequent complication of influenza and other respiratory viral infections, but the mechanisms underlying viral-induced susceptibility to bacterial infections are poorly understood. In particular, it is unclear whether the host's response against the viral infection, independent of the injury caused by the virus, results in impairment of antibacterial host defense. Here, we sought to determine whether the induction of an "antiviral" immune state using various viral recognition receptor ligands was sufficient to result in decreased ability to combat common bacterial pathogens of the lung. Using a mouse model, animals were administered polyinosine-polycytidylic acid (poly I:C) or Toll-like 7 ligand (imiquimod or gardiquimod) intranasally, followed by intratracheal challenge with Streptococcus pneumoniae. We found that animals pre-exposed to poly I:C displayed impaired bacterial clearance and increased mortality. Poly I:C-exposed animals also had decreased ability to clear methicillin-resistant Staphylococcus aureus. Furthermore, we showed that activation of Toll-like receptor (TLR)3 and Retinoic acid inducible gene (RIG-I)/Cardif pathways, which recognize viral nucleic acids in the form of dsRNA, both contribute to poly I:C mediated impairment of bacterial clearance. Finally, we determined that poly I:C administration resulted in significant induction of type I interferons (IFNs), whereas the elimination of type I IFN signaling improved clearance and survival following secondary bacterial pneumonia. Collectively, these results indicate that in the lung, poly I:C administration is sufficient to impair pulmonary host defense against clinically important gram-positive bacterial pathogens, which appears to be mediated by type I IFNs.