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¼ Negative margin resection of musculoskeletal sarcomas is associated with reduced risk of local recurrence.¼ There is limited evidence to support an absolute margin width of soft tissue or bone that correlates with reduced risk of local recurrence.¼ Factors intrinsic to the tumor, including histologic subtype, grade, growth pattern and neurovascular involvement impact margin status and local recurrence, and should be considered when evaluating a patient's individual risk after positive margins.¼ Appropriate use of adjuvant therapy, critical analysis of preoperative advanced cross-sectional imaging, and the involvement of a multidisciplinary team are essential to obtain negative margins when resecting sarcomas.
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Sarcoma , Neoplasias de Tecidos Moles , Humanos , Margens de Excisão , Sarcoma/cirurgia , Neoplasias de Tecidos Moles/cirurgia , Proliferação de Células , Terapia CombinadaRESUMO
Biliary-pattern injury in the liver (eg, duct injury, ductular reaction, cholestasis) can occur in several conditions, including primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), large duct obstruction (LDO), and drug-induced liver injury (DILI). While the histologic changes in these conditions have been individually well described, distinguishing among them remains often challenging, particularly when biopsy samples are limited in size, robust clinical information is unavailable, and/or the pathologist does not feel confident in evaluating liver disease. This study evaluated histologic features that could aid the diagnosis of biliary-pattern injury on biopsy. We reviewed 121 liver biopsies from clinically confirmed cases of PBC, PSC, chronic LDO, or DILI for multiple clinical and histologic parameters. The rates of these histologic findings were then compared among different entities. Onion-skin fibrosis was seen in 14% of PSC in comparison to 0%, 5%, and 0% of PBC, DILI, and chronic LDO (P = 0.031). Florid duct lesions were identified in 21% of PBC compared to 2% of PSC and 0% of DILI and LDO (P = 0.0065). Similarly, 42% of PBC showed lobular granulomas, compared to 7% of PSC, 11% of DILI, and 33% of chronic LDO (P = 0.0001). Cholestasis was more commonly seen in DILI (42%) and chronic LDO (83%) than in PBC (4%) and PSC (16%) (P < 0.0001). Lobular chronic inflammation was found in a significantly higher percentage of PBC and LDO than of PSC and DILI (P = 0.0009). There were significantly fewer cases of PBC showing neutrophils in ductular reaction than PSC, DILI, and LDO (P = 0.0063). Histologic findings that can help suggest a diagnosis in liver biopsies with biliary-pattern injury include florid duct lesions, lobular granulomas, lack of neutrophils in ductular reaction, and lobular chronic inflammation in PBC; onion-skin fibrosis in PSC; cholestasis and feathery degeneration in DILI; and lobular granulomas, lobular chronic inflammation, cholestasis, and feathery degeneration in chronic LDO. These findings are likely most helpful when complicating factors interfere with biopsy interpretation.
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Colangite Esclerosante , Cirrose Hepática Biliar , Fígado , Humanos , Feminino , Biópsia , Masculino , Pessoa de Meia-Idade , Fígado/patologia , Adulto , Colangite Esclerosante/patologia , Idoso , Cirrose Hepática Biliar/patologia , Colestase/patologia , Adulto Jovem , Doença Hepática Induzida por Substâncias e Drogas/patologia , Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Idoso de 80 Anos ou mais , Adolescente , Diagnóstico Diferencial , Ductos Biliares/patologiaRESUMO
BACKGROUND: The medical therapy of prostatic symptoms (MTOPS) trial randomized men with symptoms of benign prostatic hyperplasia (BPH) and followed response of treatment with a 5α-reductase inhibitor (5ARI), an alpha-adrenergic receptor antagonist (α-blocker), the combination of 5ARI and α-blocker or no medical therapy (none). Medical therapy reduced risk of clinical progression by 66% but the reasons for nonresponse or loss of therapeutic response in some patients remains unresolved. Our previous work showed that prostatic glucocorticoid levels are increased in 5ARI-treated patients and that glucocorticoids can increased branching of prostate epithelia in vitro. To understand the transcriptomic changes associated with 5ARI treatment, we performed bulk RNA sequencing of BPH and control samples from patients who received 5ARI versus those that did not. Deconvolution analysis was performed to estimate cellular composition. Bulk RNA sequencing was also performed on control versus glucocorticoid-treated prostate epithelia in 3D culture to determine underlying transcriptomic changes associated with branching morphogenesis. METHOD: Surgical BPH (S-BPH) tissue was defined as benign prostatic tissue collected from the transition zone (TZ) of patients who failed medical therapy while control tissue termed Incidental BPH (I-BPH) was obtained from the TZ of men undergoing radical prostatectomy for low-volume/grade prostatic adenocarcinoma confined to the peripheral zone. S-BPH patients were divided into four subgroups: men on no medical therapy (none: n = 7), α-blocker alone (n = 10), 5ARI alone (n = 6) or combination therapy (α-blocker and 5ARI: n = 7). Control I-BPH tissue was from men on no medical therapy (none: n = 8) or on α-blocker (n = 6). A human prostatic cell line in 3D culture that buds and branches was used to identify genes involved in early prostatic growth. Snap-frozen prostatic tissue taken at the time of surgery and 3D organoids were used for RNA-seq analysis. Bulk RNAseq data were deconvoluted using CIBERSORTx. Differentially expressed genes (DEG) that were statistically significant among S-BPH, I-BPH, and during budding and branching of organoids were used for pathway analysis. RESULTS: Transcriptomic analysis between S-BPH (n = 30) and I-BPH (n = 14) using a twofold cutoff (p < 0.05) identified 377 DEG (termed BPH377) and a cutoff < 0.05 identified 3377 DEG (termed BPH3377). Within the S-BPH, the subgroups none and α-blocker were compared to patients on 5ARI to reveal 361 DEG (termed 5ARI361) that were significantly changed. Deconvolution analysis of bulk RNA seq data with a human prostate single cell data set demonstrated increased levels of mast cells, NK cells, interstitial fibroblasts, and prostate luminal cells in S-BPH versus I-BPH. Glucocorticoid (GC)-induced budding and branching of benign prostatic cells in 3D culture was compared to control organoids to identify early events in prostatic morphogenesis. GC induced 369 DEG (termed GC359) in 3D culture. STRING analysis divided the large datasets into 20-80 genes centered around a hub. In general, biological processes induced in BPH supported growth and differentiation such as chromatin modification and DNA repair, transcription, cytoskeleton, mitochondrial electron transport, ubiquitination, protein folding, and cholesterol synthesis. Identified signaling pathways were pooled to create a list of DEG that fell into seven hubs/clusters. The hub gene centrality was used to name the network including AP-1, interleukin (IL)-6, NOTCH1 and NOTCH3, NEO1, IL-13, and HDAC/KDM. All hubs showed connections to inflammation, chromatin structure, and development. The same approach was applied to 5ARI361 giving multiple networks, but the EGF and sonic hedgehog (SHH) hub was of particular interest as a developmental pathway. The BPH3377, 5ARI363, and GC359 lists were compared and 67 significantly changed DEG were identified. Common genes to the 3D culture included an IL-6 hub that connected to genes identified in BPH hubs that defined AP1, IL-6, NOTCH, NEO1, IL-13, and HDAC/KDM. CONCLUSIONS: Reduction analysis of BPH and 3D organoid culture uncovered networks previously identified in prostatic development as being reinitiated in BPH. Identification of these pathways provides insight into the failure of medical therapy for BPH and new therapeutic targets for BPH/LUTS.
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Inibidores de 5-alfa Redutase , Hiperplasia Prostática , Masculino , Humanos , Inibidores de 5-alfa Redutase/farmacologia , Inibidores de 5-alfa Redutase/uso terapêutico , Próstata/patologia , Hiperplasia Prostática/tratamento farmacológico , Hiperplasia Prostática/genética , Hiperplasia Prostática/patologia , Procedimentos Clínicos , Glucocorticoides/farmacologia , Glucocorticoides/uso terapêutico , Interleucina-13/uso terapêutico , Interleucina-6 , Proteínas Hedgehog , Antagonistas Adrenérgicos alfa/uso terapêutico , Perfilação da Expressão Gênica , Quimioterapia Combinada , CromatinaRESUMO
BACKGROUND AND OBJECTIVES: Bone tumours are relatively rare and, as a consequence, treatment in a centre with expertise is required. Current treatment guidelines also recommend review by a specialised pathologist. Here we report on international consensus-based datasets for the pathology reporting of biopsy and resection specimens of bone sarcomas. The datasets were produced under the auspices of the International Collaboration on Cancer Reporting (ICCR), a global alliance of major (inter-)national pathology and cancer organisations. METHODS AND RESULTS: According to the ICCR's process for dataset development, an international expert panel consisting of pathologists, an oncologic orthopaedic surgeon, a medical oncologist, and a radiologist produced a set of core and noncore data items for biopsy and resection specimens based on a critical review and discussion of current evidence. All professionals involved were bone tumour experts affiliated with tertiary referral centres. Commentary was provided for each data item to explain the rationale for selecting it as a core or noncore element, its clinical relevance, and to highlight potential areas of disagreement or lack of evidence, in which case a consensus position was formulated. Following international public consultation, the documents were finalised and ratified, and the datasets, including a synoptic reporting guide, were published on the ICCR website. CONCLUSION: These first international datasets for bone sarcomas are intended to promote high-quality, standardised pathology reporting. Their widespread adoption will improve the consistency of reporting, facilitate multidisciplinary communication, and enhance comparability of data, all of which will help to improve management of bone sarcoma patients.
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Patologia Clínica , Sarcoma , Humanos , Oncologia , BiópsiaRESUMO
Prognostic factors for pleomorphic dermal sarcoma, a rare undifferentiated neoplasm of the skin, are poorly defined, and typical staging systems do not appear to be appropriate for these neoplasms. We; therefore, sought to identify prognostic factors for disease-specific survival and predictors of metastasis.Pleomorphic dermal sarcomas were identified in the Surveillance, Epidemiology and End Results database (N=1911). Multiple imputation was used to overcome inherent limitations in this dataset to assess prognostic factors using multivariable Cox proportional hazard stratified by (neo)adjuvant radiotherapy and logistic regression for presentation with metastasis.Age, tumour size and metastasis were independent prognostic factors for cutaneous sarcoma-specific survival. Only tumour size was associated with increased odds of presentation with metastasis, with tumours >4 cm at highest risk. Metastasis is the most important factor in determining outcomes, with age and size as lesser factors. Only tumour size is predictive of metastasis, with larger tumours at highest risk.
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Neoplasias Ósseas , Sarcoma , Neoplasias Cutâneas , Humanos , Prognóstico , Neoplasias Cutâneas/terapia , Neoplasias Cutâneas/patologia , Neoplasias Ósseas/patologia , Sarcoma/terapia , Sarcoma/patologia , Estadiamento de NeoplasiasRESUMO
Background: Radiation after resection of an atypical lipomatous tumor (ALT) is controversial. This study evaluates local control and complications after the first resection of ALTs of the extremity with or without adjuvant radiation. Methods: A dual institution, retrospective review of patients treated from 1995 to 2020 with first-time resection of an ALT in the extremity was performed. In total, 102 patients underwent adjuvant radiation (XRT group) and 68 patients were treated with surgery alone (no-XRT group). The median follow-up time was 4.6 years (interquartile range (IQR) 2.0-7.3 years). The median radiation dose was 60 Gy (IQR 55-66 Gy). Univariable and multivariable analyses evaluated the association of patient, tumor, and treatment variables with recurrence and complications. Kaplan-Meier analysis evaluated local recurrence-free survival (LRFS) and time to complication. Results: The overall incidence of local recurrence was 1% (1/102) in the XRT group and 24% (16/68) in the no-XRT group (p < 0.001). The median time-to-recurrence was 8.2 years (IQR 6.5-10.5 years). In the XRT and the no-XRT groups, 5-yr LRFS was 98% and 92% (p=0.21) and 10-yr LRFS was 98% and 41% (p < 0.001), respectively. The absence of radiation (HR = 23.63, 95% CI (3.09-180.48); p < 0.001) and R2 surgical resection margins (HR = 11.04, 95% CI (2.07-59.03); p < 0.001) incurred a 23-fold and 11-fold increased risk of local recurrence, respectively, while tumor size, depth, location, and neurovascular involvement were not found to be independent predictors of recurrence. The complication rate was 37% (38/102) in the XRT group and 10% (7/68) in the no-XRT group (p < 0.001). Eight patients (8/102, 8%) required surgical management for complication in the XRT group compared with two patients (2/68, 3%) in the no-XRT group (p=0.10). Higher radiation dose had a modest correlation with increased severity of complication (ρ=0.24; p=0.02). Conclusions: Adjuvant radiation after first-time resection of an ALT of the extremity was associated with a significantly reduced risk of local recurrence but a three-fold increase in complication rate. These data support a 10-year follow-up for these patients and inform a notable clinical trade-off if considering adjuvant radiation for this tumor with recurrent potential.
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BACKGROUND: The development of benign prostatic hyperplasia (BPH) and medication-refractory lower urinary tract symptoms (LUTS) remain poorly understood. This study attempted to characterize the pathways associated with failure of medical therapy for BPH/LUTS. METHODS: Transitional zone tissue levels of cholesterol and steroids were measured in patients who failed medical therapy for BPH/LUTS and controls. Prostatic gene expression was measured using qPCR and BPH cells were used in organoid culture to study prostatic branching. RESULTS: BPH patients on 5-α-reductase inhibitor (5ARI) showed low levels of tissue dihydrotestosterone (DHT), increased levels of steroid 5-α-reductase type II (SRD5A2), and diminished levels of androgen receptor (AR) target genes, prostate-specific antigen (PSA), and transmembrane serine protease 2 (TMPRSS2). 5ARI raised prostatic tissue levels of glucocorticoids (GC), whereas alpha-adrenergic receptor antagonists (α-blockers) did not. Nuclear localization of GR in prostatic epithelium and stroma appeared in all patient samples. Treatment of four BPH organoid cell lines with dexamethasone, a synthetic GC, resulted in budding and branching. CONCLUSIONS: After failure of medical therapy for BPH/LUTS, 5ARI therapy continued to inhibit androgenesis but a 5ARI-induced pathway increased tissue levels of GC not seen in patients on α-blockers. GC stimulation of organoids indicated that the GC receptors are a trigger for controlling growth of prostate glands. A 5ARI-induced pathway revealed GC activation can serve as a master regulator of prostatic branching and growth.
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Sintomas do Trato Urinário Inferior , Hiperplasia Prostática , 3-Oxo-5-alfa-Esteroide 4-Desidrogenase , Inibidores de 5-alfa Redutase/farmacologia , Di-Hidrotestosterona/metabolismo , Glucocorticoides/metabolismo , Glucocorticoides/farmacologia , Humanos , Hiperplasia/metabolismo , Hiperplasia/patologia , Sintomas do Trato Urinário Inferior/patologia , Masculino , Proteínas de Membrana/metabolismo , Próstata/patologia , Hiperplasia Prostática/genéticaRESUMO
Risk stratification of gastrointestinal stromal tumors (GISTs) is based on experience with tumors of the stomach, small bowel, and rectum, which are far more common than GISTs of other sites. In this study from 47 institutions, we analyzed GISTs of the esophagus (n = 102), colon (n = 136), and appendix (n = 27) for their size, mitotic rate, morphology, and outcome to determine which criteria predict their behavior. Esophageal GISTs were small (median: 2.5 cm) with spindle cell morphology and a low mitotic rate (mean: 3.6/5 mm2). Twelve (12%) tumors progressed, including 11 with a mitotic rate >5/5 mm2 and one large (6.8 cm) GIST with a mitotic rate of 2/5 mm2. Colonic GISTs were smaller (median: 1.4 cm) and presented with abdominal pain or bleeding in 29% of cases. Most (92%) were composed of spindle cells with a mean mitotic rate of 4.6/5 mm2. Sixteen (12%) tumors progressed: 14 had mitotic rates >5/5 mm2, and two were >5.0 cm with a mitotic rate <5/5 mm2. All but one appendiceal GIST measured <2.0 cm. These tumors were composed of spindle cells with low mitotic rates (<5/5 mm2), and none progressed. Our results suggest that progression risk among esophageal and colonic GISTs is associated with increased mitotic activity (>5/5 mm2) and size >5.0 cm. These findings support the use of size and mitotic rate for prognostication of GISTs in these locations, similar to tumors of the stomach, small bowel, and rectum.
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Apêndice , Tumores do Estroma Gastrointestinal , Neoplasias Gástricas , Apêndice/patologia , Colo/patologia , Esôfago/patologia , Tumores do Estroma Gastrointestinal/patologia , Humanos , Medição de Risco , Neoplasias Gástricas/patologiaRESUMO
Current standard therapy for locally advanced rectal cancer (LARC) is neoadjuvant therapy followed by surgical resection; however, treatment response is variable among patients. This study aimed to identify histologic features that predict tumor response. This retrospective study included 105 patients with LARC, all of whom underwent biopsy followed by neoadjuvant therapy and subsequent surgical resection. Each patient's initial biopsy was evaluated for tumor grade, tumor budding, intraepithelial lymphocytes, intraepithelial neutrophils, desmoplasia, apoptosis, adjacent stromal lymphocytes, signet ring cells, mucinous features, tumoral Paneth cells, dirty necrosis, microscopic ulceration, and prominent lymphoid aggregates. These histologic features, along with patient age at diagnosis and tumor microsatellite status, were compared to tumor regression grades from the respective resection specimens. No histologic factors in tumor biopsies predictive of treatment response in post-therapy resection specimens were identified. Histologic features in pre-therapy biopsy samples of LARC do not predict subsequent response to neoadjuvant therapy. Effective and reliable methods to predict response to neoadjuvant therapy in rectal cancer remain elusive.
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Adenocarcinoma/patologia , Terapia Neoadjuvante/métodos , Neoplasias Retais/patologia , Resultado do Tratamento , Adenocarcinoma/terapia , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Retais/terapia , Estudos RetrospectivosRESUMO
BACKGROUND: Little is known about how benign prostatic hyperplasia (BPH) develops and why patients respond differently to medical therapy designed to reduce lower urinary tract symptoms (LUTS). The Medical Therapy of Prostatic Symptoms (MTOPS) trial randomized men with symptoms of BPH and followed response to medical therapy for up to 6 years. Treatment with a 5α-reductase inhibitor (5ARI) or an alpha-adrenergic receptor antagonist (α-blocker) reduced the risk of clinical progression, while men treated with combination therapy showed a 66% decrease in risk of progressive disease. However, medical therapies for BPH/LUTS are not effective in many patients. The reasons for nonresponse or loss of therapeutic response in the remaining patients over time are unknown. A better understanding of why patients fail to respond to medical therapy may have a major impact on developing new approaches for the medical treatment of BPH/LUTS. Prostaglandins (PG) act on G-protein-coupled receptors (GPCRs), where PGE2 and PGF2 elicit smooth muscle contraction. Therefore, we measured PG levels in the prostate tissue of BPH/LUTS patients to assess the possibility that this signaling pathway might explain the failure of medical therapy in BPH/LUTS patients. METHOD: Surgical BPH (S-BPH) was defined as benign prostatic tissue collected from the transition zone (TZ) of patients who failed medical therapy and underwent surgical intervention to relieve LUTS. Control tissue was termed Incidental BPH (I-BPH). I-BPH was TZ obtained from men undergoing radical prostatectomy for low-volume, low-grade prostatic adenocarcinoma (PCa, Gleason score ≤ 7) confined to the peripheral zone. All TZ tissue was confirmed to be cancer-free. S-BPH patients divided into four subgroups: patients on α-blockers alone, 5ARI alone, combination therapy (α-blockers plus 5ARI), or no medical therapy (none) before surgical resection. I-BPH tissue was subgrouped by prior therapy (either on α-blockers or without prior medical therapy before prostatectomy). We measured prostatic tissue levels of prostaglandins (PGF2α , PGI2 , PGE2 , PGD2 , and TxA2 ), quantitative polymerase chain reaction levels of mRNAs encoding enzymes within the PG synthesis pathway, cellular distribution of COX1 (PTGS1) and COX2 (PTGS2), and tested the ability of PGs to contract bladder smooth muscle in an in vitro assay. RESULTS: All PGs were significantly elevated in TZ tissues from S-BPH patients (n = 36) compared to I-BPH patients (n = 15), regardless of the treatment subgroups. In S-BPH versus I-BPH, mRNA for PG synthetic enzymes COX1 and COX2 were significantly elevated. In addition, mRNA for enzymes that convert the precursor PGH2 to metabolite PGs were variable: PTGIS (which generates PGI2 ) and PTGDS (PGD2 ) were significantly elevated; nonsignificant increases were observed for PTGES (PGE2 ), AKR1C3 (PGF2α ), and TBxAS1 (TxA2 ). Within the I-BPH group, men responding to α-blockers for symptoms of BPH but requiring prostatectomy for PCa did not show elevated levels of COX1, COX2, or PGs. By immunohistochemistry, COX1 was predominantly observed in the prostatic stroma while COX2 was present in scattered luminal cells of isolated prostatic glands in S-BPH. PGE2 and PGF2α induced contraction of bladder smooth muscle in an in vitro assay. Furthermore, using the smooth muscle assay, we demonstrated that α-blockers that inhibit alpha-adrenergic receptors do not appear to inhibit PG stimulation of GPCRs in bladder muscle. Only patients who required surgery to relieve BPH/LUTS symptoms showed significantly increased tissue levels of PGs and the PG synthetic enzymes. CONCLUSIONS: Treatment of BPH/LUTS by inhibition of alpha-adrenergic receptors with pharmaceutical α-blockers or inhibiting androgenesis with 5ARI may fail because of elevated paracrine signaling by prostatic PGs that can cause smooth muscle contraction. In contrast to patients who fail medical therapy for BPH/LUTS, control I-BPH patients do not show the same evidence of elevated PG pathway signaling. Elevation of the PG pathway may explain, in part, why the risk of clinical progression in the MTOPS study was only reduced by 34% with α-blocker treatment.
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Sintomas do Trato Urinário Inferior/tratamento farmacológico , Prostaglandinas/metabolismo , Próstata/metabolismo , Hiperplasia Prostática/tratamento farmacológico , Inibidores de 5-alfa Redutase/uso terapêutico , Antagonistas Adrenérgicos alfa/uso terapêutico , Idoso , Humanos , Sintomas do Trato Urinário Inferior/etiologia , Sintomas do Trato Urinário Inferior/metabolismo , Masculino , Pessoa de Meia-Idade , Hiperplasia Prostática/complicações , Hiperplasia Prostática/metabolismo , Falha de TratamentoRESUMO
BACKGROUND: Although a variety of pathological changes have been described in small airways of patients with COPD, the critical anatomic features determining airflow limitation remain incompletely characterised. METHODS: We examined lung tissue specimens from 18 non-smokers without chronic lung disease and 55 former smokers with COPD for pathological features of small airways that could contribute to airflow limitation. Morphometric evaluation was performed for epithelial and subepithelial tissue thickness, collagen and elastin content, luminal mucus and radial alveolar attachments. Immune/inflammatory cells were enumerated in airway walls. Quantitative emphysema scoring was performed on chest CT scans. RESULTS: Small airways from patients with COPD showed thickening of epithelial and subepithelial tissue, mucus plugging and reduced collagen density in the airway wall (in severe COPD). In patients with COPD, we also observed a striking loss of alveolar attachments, which are connective tissue septa that insert radially into the small airway adventitia. While each of these parameters correlated with reduced airflow (FEV1), multivariable regression analysis indicated that loss of alveolar attachments was the major determinant of airflow limitation related to small airways. Neutrophilic infiltration of airway walls and collagen degradation in airway adventitia correlated with loss of alveolar attachments. In addition, quantitative analysis of CT scans identified an association between the extent of emphysema and loss of alveolar attachments. CONCLUSION: In COPD, loss of radial alveolar attachments in small airways is the pathological feature most closely related to airflow limitation. Destruction of alveolar attachments may be mediated by neutrophilic inflammation.
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Doença Pulmonar Obstrutiva Crônica , Enfisema Pulmonar , Humanos , Pulmão/diagnóstico por imagem , Doença Pulmonar Obstrutiva Crônica/diagnóstico por imagem , Enfisema Pulmonar/diagnóstico por imagem , Testes de Função Respiratória , Fenômenos Fisiológicos RespiratóriosRESUMO
Tumor budding (TB) has been shown to be an adverse prognostic factor in several gastrointestinal malignancies, most notably colorectal carcinoma (CRC). TB has undergone some evaluation in Eastern cohorts of cholangiocarcinoma (CC), and we undertook this study to evaluate whether TB in CC was linked to other clinicopathologic factors or to outcome in a Western cohort. We evaluated 112 cases of CC for age, sex, margin status, location, size, grade, lymphovascular invasion (LVI), perineural invasion (PNI), subtype (large or small duct), staging parameters, recurrence-free survival, disease-specific survival (DSS), and TB. Budding was scored using International Tumor Budding Consensus Conference recommendations for CRC: The highest tumor bud count at the invasive tumor front in a 0.785 mm2 area was recorded and stratified into Bd1 (0-4 buds), Bd2 (5-9 buds), and Bd3 (≥10 buds). Our cohort included 54 (48%) extrahepatic CCs and 58 (52%) intrahepatic CCs. TB was more commonly seen in the settings of higher-grade lesions, males, extrahepatic CC, PNI, LVI, and positive resection margin (all P ≤ 0.021). In multivariate analysis, worse DSS was correlated with budding score Bd2/Bd3 (hazard ratio [HR] 2.6687, 95% confidence interval [CI] 1.585-5.217, P = 0.001) and with nodal disease (HR 2.876, 95% CI 1.585-5.217, P = 0.001). TB is associated with higher-grade disease in CC, and increased TB is associated with poor disease-specific survival. Our findings support the notion that TB may serve as useful information for clinicians with respect to patient prognosis in CC, as in CRC.
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Neoplasias dos Ductos Biliares/patologia , Colangiocarcinoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias dos Ductos Biliares/mortalidade , Colangiocarcinoma/mortalidade , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , PrognósticoRESUMO
AIMS: Appendiceal well-differentiated neuroendocrine tumours (NETs) are usually incidental and clinically benign. Several studies have reported different risk factors for nodal metastasis. The aim of this study was to investigate our appendiceal NETs (App-NETs) to determine the factors associated with malignant behaviour. METHODS AND RESULTS: For 120 App-NETs, we reviewed the clinical presentation and follow-up, including serum chromogranin A (CgA) levels, and compiled several microscopic variables. Pathological factors were compared with nodal status and time to biochemical recurrence (elevated serum CgA level) by the use of Cox regression. We also reviewed similar App-NET data in the Surveillance, Epidemiology, and End Results (SEER) Programme. Among our 120 cases, seven patients had positive lymph nodes, and nine developed subsequent elevation of CgA levels; none developed distant metastases or died of disease. Only three patients had grade 2 NETs; none had nodal disease, and one developed an elevated CgA level. Increasing tumour size was associated with an increased risk of nodal disease [odds ratio (OR) 4.99, P = 0.0055). All seven node-positive cases were ≥13 mm. Factors associated with elevated CgA levels included age (OR 1.04, P = 0.041), pT4 disease (OR 10.22, P = 0.033), and nodal disease (OR 24.0, P = 0.012), but not size (OR 2.13, P = 0.072). Of the 1492 reported App-NETs in the SEER database with data on tumour size, 137 (9%) were pN1; only five of these (4%) were coded as being <5 mm. CONCLUSIONS: Small (<5 mm) App-NETs that do not invade the serosa or mesoappendix appear to be overwhelmingly benign and low-grade, requiring neither Ki67 staining nor synoptic reporting. Given their indolent behaviour, different nomenclature or staging may be more appropriate for these NETs.
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Neoplasias do Apêndice/patologia , Neoplasias Intestinais/patologia , Tumores Neuroendócrinos/patologia , Neoplasias Pancreáticas/patologia , Neoplasias Gástricas/patologia , Apendicectomia , Apêndice/patologia , Feminino , Humanos , Antígeno Ki-67/análise , Metástase Linfática/patologia , Masculino , Estadiamento de Neoplasias , Prognóstico , Fatores de RiscoRESUMO
Soft tissue sarcomas arising in visceral organs are rare and lack validated tumor-staging protocols. Clinicopathologic features and clinical outcomes of 2698 visceral sarcomas identified in the Surveillance, Epidemiology, and End Results Program (SEER) database were compared with sarcomas arising in the extremities/trunk (n = 10,237) or retroperitoneum (n = 1067) using standard statistical techniques. Important prognostic criteria for visceral sarcomas, as in other anatomic sites, included tumor size, histologic grade, and presence of metastatic disease. After adjustment for pertinent confounding factors, visceral sarcomas showed cancer-specific survival rates similar to those arising in the retroperitoneum but had worse outcomes than sarcomas in the extremities/trunk. Therefore, the prognostic performance of two different staging algorithms for retroperitoneal sarcomas was evaluated for their use in staging sarcomas of visceral organs. The current AJCC 8th edition and the recently derived Vanderbilt system for staging retroperitoneal sarcoma both showed adequate discrimination, as assessed by multiple clinical concordance indices, and no evidence of miscalibration. Therefore, the authors concluded that previously validated staging systems for retroperitoneal sarcomas based on conventional prognostic factors (histologic grade, tumor size, and presence of metastatic disease) are applicable to visceral sarcomas and should be incorporated into the next edition of the AJCC Cancer Staging Manual.
Assuntos
Neoplasias Retroperitoneais , Sarcoma , Neoplasias de Tecidos Moles , Humanos , Estadiamento de Neoplasias , Prognóstico , Neoplasias Retroperitoneais/epidemiologia , Neoplasias Retroperitoneais/patologia , Medição de Risco , Programa de SEER , Sarcoma/epidemiologia , Sarcoma/patologia , Neoplasias de Tecidos Moles/patologiaRESUMO
Despite the release of anatomic site-specific staging systems for soft tissue sarcomas in the eighth edition of the American Joint Committee on Cancer (AJCC) Cancer Staging Manual, the algorithms for sarcomas arising in the extremities/trunk and retroperitoneum differ only in the staging of lymph node metastasis. The retroperitoneum not only provides a larger potential space for tumor growth before the clinical presentation, but its anatomic complexities complicate surgical resection and adversely affect disease-free survival. Here, we propose a new staging system for MDM2-amplified liposarcomas (well-differentiated and dedifferentiated subtypes) that properly emphasizes retroperitoneal localization, degree of differentiation (histologic subtype), and presence of distant metastasis. A retrospective cohort of 4146 adult patients with surgically resected liposarcoma was extracted from the SEER database to compare the natural history of MDM2-amplified liposarcomas arising in the extremities/trunk or retroperitoneum. Separate training and validation datasets were created, and Cox proportional hazard regression, multivariable nonlinear regression, and nomographic analyses determined the most significant parameters in predicting sarcoma-specific death. A new staging system was derived and its predictive accuracy was compared with the AJCC, eighth edition system using areas under receiver operating characteristic curves and multiple concordance indices. Multivariable analysis showed that dedifferentiation (hazard ratio [HR]=3.7±0.5; P<0.0005), retroperitoneal location (HR=3.2±0.5; P<0.0005), and distant metastasis (HR=2.4±0.6; P=0.002), but not categorized tumor size (pT category), had the largest effects on sarcoma-specific survival. A new staging system based on these predictive factors demonstrated better discrimination between tumor stages, higher concordance with clinical outcomes, and greater predictive accuracy than the AJCC eighth edition staging system (86±1% vs. 83±2%; P=0.005). Statistical analysis of a large national cohort failed to confirm that categorized tumor size is a useful criterion by which to stage MDM2-amplified liposarcoma. A simplified staging system based on anatomic location and dedifferentiation outperforms the current AJCC staging system. Anatomic localization and histologic grade, and not tumor size, should be included in any future liposarcoma-specific staging system.
Assuntos
Lipossarcoma/patologia , Estadiamento de Neoplasias/métodos , Neoplasias de Tecidos Moles/patologia , Idoso , Intervalo Livre de Doença , Feminino , Amplificação de Genes , Humanos , Lipossarcoma/genética , Lipossarcoma/mortalidade , Masculino , Pessoa de Meia-Idade , Prognóstico , Proteínas Proto-Oncogênicas c-mdm2/genética , Estudos Retrospectivos , Programa de SEER , Neoplasias de Tecidos Moles/genética , Neoplasias de Tecidos Moles/mortalidadeRESUMO
BACKGROUND: Most prostate cancers express androgen receptor (AR), and our previous studies have focused on identifying transcription factors that modify AR function. We have shown that nuclear factor I/B (NFIB) regulates AR activity in androgen-dependent prostate cancer cells in vitro. However, the status of NFIB in prostate cancer was unknown. METHODS: We immunostained a tissue microarray including normal, hyperplastic, prostatic intraepithelial neoplasia, primary prostatic adenocarcinoma, and castration-resistant prostate cancer tissue samples for NFIB, AR, and synaptophysin, a marker of neuroendocrine differentiation. We interrogated publically available data sets in cBioPortal to correlate NFIB expression and AR and neuroendocrine prostate cancer (NEPCa) activity scores. We analyzed prostate cancer cell lines for NFIB expression via Western blot analysis and used nuclear and cytoplasmic fractionation to assess where NFIB is localized. We performed co-immunoprecipitation studies to determine if NFIB and AR interact. RESULTS: NFIB increased in the nucleus and cytoplasm of prostate cancer samples versus matched normal controls, independent of Gleason score. Similarly, cytoplasmic AR and synaptophysin increased in primary prostate cancer. We observed strong NFIB staining in primary small cell prostate cancer. The ratio of cytoplasmic-to-nuclear NFIB staining was predictive of earlier biochemical recurrence in prostate cancer, once adjusted for tumor margin status. Cytoplasmic AR was an independent predictor of biochemical recurrence. There was no statistically significant difference between NFIB and synaptophysin expression in primary and castration-resistant prostate cancer, but cytoplasmic AR expression was increased in castration-resistant samples. In primary prostate cancer, nuclear NFIB expression correlated with cytoplasmic NFIB and nuclear AR, while cytoplasmic NFIB correlated with synaptophysin, and nuclear and cytoplasmic AR. In castration-resistant prostate cancer samples, NFIB expression correlated positively with an AR activity score, and negatively with the NEPCa score. In prostate cancer cell lines, NFIB exists in several isoforms. We observed NFIB predominantly in the nuclear fraction of prostate cancer cells with increased cytoplasmic expression seen in castration-resistant cell lines. We observed an interaction between AR and NFIB through co-immunoprecipitation experiments. CONCLUSION: We have described the expression pattern of NFIB in primary and castration-resistant prostate cancer and its positive correlation with AR. We have also demonstrated AR interacts with NFIB.
Assuntos
Fatores de Transcrição NFI/biossíntese , Neoplasias de Próstata Resistentes à Castração/metabolismo , Neoplasias da Próstata/metabolismo , Receptores Androgênicos/biossíntese , Linhagem Celular Tumoral , Expressão Gênica , Humanos , Imuno-Histoquímica , Masculino , Fatores de Transcrição NFI/genética , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/patologia , Receptores Androgênicos/genética , Análise Serial de Tecidos , TranscriptomaRESUMO
The development of pulmonary metastasis is the leading cause of death in osteosarcoma (OS), which is the most common malignant bone tumor in children. We have previously reported that the tumor suppressor p27 (KIP1, CDKN1B) is frequently mislocalized to the cytoplasm of OS. However, its prognostic significance and metastatic mechanism are still elusive. Here, we show that cytoplasmic p27 significantly correlated with a higher metastatic status and poorer survival of OS patients (n = 136, P < 0.05), highlighting the clinical significance of p27 mislocalization in OS. Mechanistically, cytoplasmic p27 is co-immunoprecipitated with p21-activated kinase 1 (PAK1), which resulted in higher PAK1 phosphorylations, actin polymerization, and cell motility in p27-mislocalized OS cells. Silencing PAK1 expression in different p27-mislocalized OS cell lines decreased the migratory and adhesion abilities in vitro, as well as the development of pulmonary metastases in vivo. Similar PAK1-dependent motility was also observed in other p27-mislocalized cancer cell lines. In summary, our study suggests that cytoplasmic p27-mediated PAK1 activation is crucial for OS metastasis. A biomarker-guided targeted therapeutic approach for metastatic OS and other cancers harboring p27 mislocalization can be developed, where cytoplasmic p27 is used for risk stratification and PAK1 can be exploited as a potential therapeutic target.
Assuntos
Neoplasias Ósseas/patologia , Inibidor de Quinase Dependente de Ciclina p27/metabolismo , Neoplasias Pulmonares/secundário , Osteossarcoma/patologia , Quinases Ativadas por p21/metabolismo , Adolescente , Adulto , Animais , Neoplasias Ósseas/diagnóstico , Neoplasias Ósseas/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Inibidor de Quinase Dependente de Ciclina p27/análise , Citoplasma/metabolismo , Citoplasma/patologia , Ativação Enzimática , Feminino , Humanos , Neoplasias Pulmonares/metabolismo , Masculino , Camundongos , Osteossarcoma/diagnóstico , Osteossarcoma/metabolismo , Prognóstico , Mapas de Interação de Proteínas , Adulto JovemRESUMO
GATA3 is a transcription factor involved in the development and differentiation of lymphocytes, breast, and hair follicles. The protein is a useful immunohistochemical (IHC) marker for supporting diagnoses of breast or urothelial carcinoma. This can be especially helpful in metastatic neoplasms to help delineate site of origin. GATA3 is also reportedly positive in a percentage of pancreatic ductal adenocarcinomas (PDACs) and cholangiocarcinomas (CCs), but no study has closely evaluated this relationship with respect to clininopathologic features or patient outcome. Using tissue microarrays, we analyzed 240 PDACs and 60 CCs with GATA3 IHC and compared expression to various clinical and pathologic parameters. Overall, GATA3 positivity was seen in 16% of PDACs and 5% of CCs. GATA3 positivity in PDAC cases was more common in male patients (P=0.013). GATA3-positive PDACs trended toward worse survival on multivariate analysis (P=0.074). The only 3 GATA3-positive CCs were poorly differentiated (P=0.069); low case number precluded multivariate survival analysis for CCs. GATA3 positivity can occur in carcinomas of the pancreatobiliary system, which should be considered during IHC workup of neoplasms of unclear origin. This positivity seems to have minimal relevance to patient outcome.
Assuntos
Neoplasias dos Ductos Biliares/metabolismo , Carcinoma Ductal Pancreático/metabolismo , Diferenciação Celular , Colangiocarcinoma/metabolismo , Fator de Transcrição GATA3/metabolismo , Neoplasias Pancreáticas/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Biópsia , Carcinoma Ductal Pancreático/mortalidade , Colangiocarcinoma/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Neoplasias Pancreáticas/mortalidadeRESUMO
The eighth edition of the American Joint Committee on Cancer (AJCC) staging system has introduced major changes for the staging of skeletal sarcomas. However, it is unclear if these changes improve the predictive value for chondrosarcomas of the nonpelvic appendicular and nonspinal axial skeleton. Specifically, there is no clear evidence that supports the use of the proposed binary size cutoff of 8 cm for risk stratification, nor is a rationale provided for the categorization of grade 2 chondrosarcomas as high grade. The prognostic value of various anatomic and pathologic factors including tumor size, histologic grade, site of metastasis, and local tumor extent was evaluated using a cohort of patients derived from the National Cancer Database (N=3946). A simplified evidence-based staging system for chondrosarcoma (the Vanderbilt Staging System) was developed based on histologic subtype, histologic grade, and presence of metastatic disease. The predictive accuracy for 5-year overall survival was evaluated for the AJCC 8th edition, Musculoskeletal Tumor Society, and Vanderbilt Staging Systems by comparing areas under receiver operating characteristic curves generated from logistic regression analysis. Three different concordance indices and Bayesian information criterion were also calculated for model comparisons. The Vanderbilt Staging System showed significantly improved predictive accuracy for 5-year survival (82±2%) compared with the AJCC (79±2%; P=0.0075) and Musculoskeletal Tumor Society systems (76±2%; P<0.00005) in a separate validation cohort. Furthermore, the Vanderbilt Staging System showed significantly higher concordance with clinical outcomes for 2 of 3 examined indices and significantly greater extent of explained variation compared with the other 2 staging systems.