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CONTEXT: Rapid on-site evaluation (ROSE) optimises the performance of cytology, but requires skilled handling, and smearing can make the material unavailable for some ancillary tests. There is a need to facilitate ROSE without sacrificing part of the sample. OBJECTIVE: We evaluated the image quality of inexpensive deconvolution fluorescence microscopy for optically sectioning non-smeared fine needle aspiration (FNA) tissue fragments. DESIGN: A portion of residual material from 14 FNA samples was stained for 3 min in Hoechst 33342 and Sypro™ Red to label DNA and protein respectively, transferred to an imaging chamber, and imaged at 200× or 400× magnification at 1 micron intervals using a GE DeltaVision inverted fluorescence microscope. A deconvolution algorithm was applied to remove out-of-plane signal, and the resulting images were inverted and pseudocoloured to resemble H&E sections. Five cytopathologists blindly diagnosed 2 to 4 representative image stacks per case (total 70 evaluations), and later compared them to conventional epifluorescent images. RESULTS: Accurate definitive diagnoses were rendered in 45 (64%) of 70 total evaluations; equivocal diagnoses (atypical or suspicious) were made in 21 (30%) of the 70. There were two false positive and two false negative "definite" diagnoses in three cases (4/70; 6%). Cytopathologists preferred deconvolved images compared to raw images (P < 0.01). The imaged fragments were recovered and prepared into a ThinPrep or cell block without discernible alteration. CONCLUSIONS: Deconvolution improves image quality of FNA fragments compared to epifluorescence, often allowing definitive diagnosis while enabling the ROSE material to be subsequently triaged.
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Microscopia , Avaliação Rápida no Local , Biópsia por Agulha Fina/métodos , Citodiagnóstico , Técnicas Citológicas , HumanosRESUMO
Dedifferentiated carcinoma is defined as undifferentiated carcinoma coexisting with a second component of FIGO grade 1 or 2 endometrioid carcinoma. It is a rare entity with highly aggressive behavior. Dedifferentiated carcinoma combined with another primary uterine tumor is even rarer. We describe a case containing 3 different morphologies comprised of a dedifferentiated carcinoma associated with a low-grade endometrioid carcinoma coexisting with a low-grade Müllerian adenosarcoma. We also used targeted genomic analysis to show all 3 components arise from the same founding clone and identify novel mutations that drive tumor progression.
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Adenossarcoma/patologia , Carcinoma Endometrioide/patologia , Neoplasias do Endométrio/patologia , Neoplasias Primárias Múltiplas/patologia , Neoplasias Uterinas/patologia , Adenossarcoma/genética , Idoso , Carcinoma Endometrioide/genética , Neoplasias do Endométrio/genética , Evolução Fatal , Feminino , Humanos , Imuno-Histoquímica , Neoplasias Primárias Múltiplas/genética , Neoplasias Uterinas/genéticaRESUMO
Overlapping morphologic, immunohistochemical, and ultrastructural features make it difficult to diagnose chromophobe renal cell carcinoma (ChRCC) and renal oncocytoma (RO). Because ChRCC is a malignant tumor, whereas RO is a tumor with benign behavior, it is important to distinguish these two entities. We aimed to identify genetic markers that distinguish ChRCC from RO by using next-generation sequencing (NGS). NGS for hotspot mutations or gene copy number changes was performed on 12 renal neoplasms, including seven ChRCC and five RO cases. Matched normal tissues from the same patients were used to exclude germline variants. Rare hotspot mutations were found in cancer-critical genes (TP53 and PIK3CA) in ChRCC but not RO. The NGS gene copy number analysis revealed multiple abnormalities. The two most common deletions were tumor-suppressor genes RB1 and ERBB4 in ChRCC but not RO. Fluorescence in situ hybridization was performed on 65 cases (ChRCC, n = 33; RO, n = 32) to verify hemizygous deletion of RB1 (17/33, 52%) or ERBB4 (11/33, 33%) in ChRCC, but not in RO (0/32, 0%). In total, ChRCCs (23/33, 70%) carry either a hemizygous deletion of RB1 or ERBB4. The combined use of RB1 and ERBB4 fluorescence in situ hybridization to detect deletion of these genes may offer a highly sensitive and specific assay to distinguish ChRCC from RO.
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Adenoma Oxífilo/genética , Carcinoma de Células Renais/genética , Deleção de Genes , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Neoplasias Renais/genética , Receptor ErbB-4/genética , Proteínas de Ligação a Retinoblastoma/genética , Ubiquitina-Proteína Ligases/genética , Adenoma Oxífilo/diagnóstico , Adulto , Idoso , Carcinoma de Células Renais/diagnóstico , Diagnóstico Diferencial , Feminino , Genes Supressores de Tumor , Humanos , Neoplasias Renais/diagnóstico , Masculino , Pessoa de Meia-Idade , OncogenesRESUMO
AIMS: Pulmonary Langerhans cell histiocytosis (PLCH) is an idiopathic cigarette smoking-related disorder of the lung. Molecular changes in cellular or fibrotic stages of PLCH have not been investigated. We studied the prevalence of extracellular signal-regulated kinase (ERK) pathway mutations in different PLCH stages and other non-PLCH smoking-related lung diseases. METHODS AND RESULTS: The cohort included 28 PLCH with cellular (n = 10), mixed cellular/fibrotic (n = 4) and fibrotic histology (n = 14). Seven cases had concurrent multi-focal/multi-lobar tumours. Respiratory bronchiolitis interstitial lung disease (RB-ILD, n = 2), desquamative interstitial pneumonia (DIP, n = 4) and mixed RB-ILD/DIP (n = 2) were included for comparison. BRAF(V) (600E) immunohistochemistry, next-generation sequencing (NGS) and peptide nucleic acid (PNA) clamp polymerase chain reaction (PCR) with high analytical sensitivity (<0.1-0.2%) were used to analyse RAS, BRAF and MAP2K1 genes. Of 26 cases with gene mutation data, BRAF(V) (600E) was identified in eight of 12 (67%) cellular cases and in one of 14 (7%) fibrotic cases. MAP2K1 or KRAS mutations were observed in four of 14 (29%) fibrotic cases and three of the 12 (25%) cellular cases. Multi-focal/multi-lobar specimens carried identical BRAF (n = 5) or non-hotspot MAP2K1 (n = 2) mutations. The other smoking-related disorders were negative for mutations. Patients with cellular lesions or BRAF mutation were significantly younger than patients with fibrotic or BRAF wild-type PLCH. CONCLUSION: The presence of identical but mutually exclusive ERK pathway mutations in multi-focal PLCH supports a neoplastic/clonal origin for this disease. Patient age and mutation type differed between cellular and fibrotic histology and may indicate a natural progression or a mutation-specific pathogenicity.
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Histiocitose de Células de Langerhans/genética , Pneumopatias/genética , Sistema de Sinalização das MAP Quinases/genética , Adolescente , Adulto , Idoso , Análise Mutacional de DNA , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Histiocitose de Células de Langerhans/etiologia , Histiocitose de Células de Langerhans/patologia , Humanos , Imuno-Histoquímica , Pneumopatias/etiologia , Pneumopatias/patologia , MAP Quinase Quinase 1/genética , Masculino , Pessoa de Meia-Idade , Mutação , Reação em Cadeia da Polimerase , Proteínas Proto-Oncogênicas B-raf/genética , Reação em Cadeia da Polimerase em Tempo Real , Fumar/efeitos adversos , Adulto Jovem , Proteínas ras/genéticaRESUMO
Published data on combined breast and gynecologic [breast/gyn] surgical pathology fellowship training programs are limited. Our study aimed to survey the landscape of such fellowships in the United States (US), including specific information about their characteristics and the educational activities therein. Using web searches, we identified programs offering combined breast/gyn surgical pathology fellowship training. We developed a 26-item questionnaire asking program directors to report on the characteristics of their fellowship training structure. The search revealed 25 academic based programs offering one-year combined breast/gyn fellowship training, predominantly located (40 %) in the Northeast area. The following data was obtained: 44 % of the programs were accredited by the ACGME, 82 % required >19 weeks of breast and gyn service, and 69.6 % accepted the common application, 54.5 % of programs require completion of a research project for graduation. An annual average of 3000 breast and 3000 gyn cases appears to be the usual volume of cases. Interestingly, only 36 % of the program directors are graduates of a combined breast/gyn fellowship program. In conclusion, we present the most comprehensive and up-to-date census of combined breast/gyn pathology fellowships in the US. Our study provides valuable information on the current state of combined breast/gyn pathology fellowship training. The information will be helpful to current and prospective trainees, as well as program leaders.
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Primary melanocytic neoplasms of the central nervous system (CNS) are uncommon and must be distinguished from metastatic lesions as patients with metastatic disease carry a worse prognosis. Therefore, tools to aid in the diagnosis of a primary CNS melanocytic neoplasm would be of clinical utility. Primary CNS melanocytic neoplasms, including uveal melanomas have frequent mutations in GNAQ and GNA11, but are rare in cutaneous and mucosal melanomas. Additionally, primary uveal melanomas often exhibit monosomy 3 conferring an elevated risk of metastasis. We present a 63 year-old male with a melanocytic neoplasm in the thoracic spinal cord. Molecular studies revealed the tumor contained a GNAQ mutation and four-color fluorescent in situ hybridization (FISH) composed of chromosome enumeration probes for 3, 7, 17 and a locus specific probe for 9p21/CDKN2A yielded a normal result (i.e. two copies per cell), favoring a primary versus metastatic melanocytic neoplasm of the CNS. We report a case in which the combination of mutational analysis and FISH aided in identifying the origin of the neoplasm.
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Neoplasias do Sistema Nervoso Central/patologia , Melanócitos/patologia , Melanoma/patologia , Neoplasias do Sistema Nervoso Central/genética , Neoplasias do Sistema Nervoso Central/secundário , Análise Mutacional de DNA , Diagnóstico Diferencial , Humanos , Masculino , Melanoma/genética , Melanoma/secundário , Pessoa de Meia-IdadeAssuntos
Adenocarcinoma/secundário , Histiócitos/patologia , Histiocitose/patologia , Neoplasias Pulmonares/patologia , Vasos Linfáticos/patologia , Neoplasias Cutâneas/secundário , Adenocarcinoma/química , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma de Pulmão , Idoso , Biomarcadores Tumorais/análise , Biópsia , Feminino , Histiócitos/química , Histiocitose/metabolismo , Humanos , Imuno-Histoquímica , Neoplasias Pulmonares/química , Neoplasias Pulmonares/tratamento farmacológico , Vasos Linfáticos/química , Neoplasias Cutâneas/química , Neoplasias Cutâneas/tratamento farmacológico , Resultado do Tratamento , Extremidade SuperiorRESUMO
This systematic review attempts to retrieve and report the findings of postmortem studies including the histopathologic data of deceased coronavirus disease 2019 patients and to review the manifestations of coronavirus disease 2019-associated thrombotic pathologies reported in the recent literature. DATA SOURCES: PubMed, Excerpta Medica Database, and Cochrane library between December 1, 2019, and August 26, 2020. STUDY SELECTION: Investigators screened 360 unique references, retrieved published autopsy series, and report on the postmortem histopathologic information on patients who had died of coronavirus disease 2019. DATA EXTRACTION: Investigators independently abstracted all available data including study design, participant demographics, key histopathologic findings, disease severity markers, duration of hospital stay, and cause of death. DATA SYNTHESIS: From the 65 eligible studies, 691 total completed autopsies were included in evidence synthesis. Histopathologic evaluation of the lungs revealed presence of diffuse alveolar damage in 323 of 443 patients and pulmonary microthrombi in 242 of 326 patients. Deep venous thrombosis and pulmonary embolism were found in 41% and ~15%, respectively, of the cadavers examined for thromboembolic events. d-dimer levels were generally higher in patients with severe clinical course of coronavirus disease 2019. Plasma levels of ferritin, lactate dehydrogenase, interleukin-6, and C-reactive protein were higher in nonsurvivors when compared with survivors. Overall, microthrombi and extensive angiogenesis of lung vasculature were the most common pathologic findings in the lungs and microthrombi in most of the assessed organ-tissue. CONCLUSIONS: Diffuse alveolar damage was the most predominant feature in the lungs of coronavirus disease 2019 patients who underwent postmortem assessment. Widespread pulmonary microthrombosis and extensive pulmonary angiogenesis, in addition to frequent pulmonary and extrapulmonary microthrombotic and thromboembolic findings in patients with coronavirus disease 2019, appear to be consistent with the disease-specific hypercoagulability. Further discovery efforts in assessing the link between coronavirus disease 2019, hypercoagulable state, and immunothrombosis are warranted. In the interim, increased attention to anticoagulant treatment approaches in coronavirus disease 2019 patients is needed.
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BACKGROUND: Urine cytology can reliably diagnose high-grade urothelial carcinoma (HGUC) but not low-grade urothelial carcinoma (LGUC), and a more sensitive test is needed. Previously, a pilot study highlighted the possible diagnostic utility of next-generation sequencing (NGS) in identifying both LGUC and HGUC in urine cytology specimens. METHODS: Twenty-eight urine ThinPrep cytology specimens and preceding or subsequent bladder tumor biopsy/resection specimens obtained within 3 months were included in the study (LGUC, n = 15; HGUC, n = 13). A customized, bladder-specific NGS panel was performed; it covered 69 frequently mutated or altered genes in urothelial carcinoma (UC) that were reported by The Cancer Genome Atlas and the Catalogue of Somatic Mutations in Cancer. RESULTS: The sequencing results were compared between the urine cytology specimens and the corresponding bladder tumor biopsies/resections. TP53 was the most frequently identified mutation in HGUC cases (11 of 13 [85%]). PIK3CA and KDM6A were the most frequently identified mutations in LGUC: they occurred in 7 of 15 cases (47%) and in 6 of 15 cases (40%), respectively. Additional frequent mutations identified in the panel included ARID1A (n = 5), EP300 (n = 4), LRP1B (n = 3), ERBB2 (n = 2), STAG2 (n = 2), FGFR3 (n = 3), MLL (n = 2), MLL3 (n = 2), CREBBP1 (n = 1), RB1 (n = 1), and FAT4 (n = 1). Overall, the concordance between the cytology and surgical specimens was 75%. The sensitivity and specificity for identifying mutations in urine cytology specimens were 84% and 100%, respectively. CONCLUSIONS: A bladder-specific NGS panel increases the sensitivity and specificity of urine cytology's diagnostic utility in both low- and high-grade tumors and may serve as a noninvasive surveillance method in the follow-up of patients with UC harboring known mutations.
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Carcinoma de Células de Transição/diagnóstico , Carcinoma de Células de Transição/genética , Sequenciamento de Nucleotídeos em Larga Escala , Neoplasias da Bexiga Urinária/diagnóstico , Neoplasias da Bexiga Urinária/genética , Bexiga Urinária/patologia , Urina/citologia , Idoso , Carcinoma de Células de Transição/patologia , Feminino , Humanos , Masculino , Neoplasias da Bexiga Urinária/patologiaRESUMO
INTRODUCTION: Colposcopic endocervical brushing cytology (CEB) is more sensitive than endocervical curettage (ECC) for detecting squamous intraepithelial lesions. There are no data on performance of CEB for detecting endocervical adenocarcinoma. MATERIALS AND METHODS: A total of 151 patients were identified in a word search for "endocervical adenocarcinoma" in surgical pathology reports from January 2007 to June 2019. To measure sensitivity, reports of CEB or ECC samples within 1 year preceding the first surgical pathology diagnosis of at least endocervical adenocarcinoma in situ (AIS+) were examined. Specificity was measured in a cohort in which at least atypical glandular cells (AGC+) was reported in CEB or ECC. RESULTS: Seven CEB preceding diagnosis of AIS were identified: 6 of 7 were positive or suspicious for AIS+. One of 7 was negative and it was negative on re-review. Three of 6 positive CEB cases used cell blocks with immunohistochemistry. Seventy ECC samples preceding diagnosis of AIS were identified: 40 of 70 were diagnosed as AGC+. The sensitivities of CEB and ECC for detecting AIS+ at a threshold of AGC+ are 86% and 57% (too few patients for statistics), respectively. For specificity, 12 of 18 CEB and 9 of 25 ECC reports with AGC+ were false positive by follow-up surgical pathology. The specificities of CEB and ECC are 99.4% and 99.9%, respectively. CONCLUSION: Sensitivity of CEB for detecting AIS+ (86%) is at least as high as ECC (57%). Specificity of CEB is similar to ECC. Addition of a cell block to CEB may be useful. CEB appears to be an appropriate test for follow-up of atypical glandular cells reported on Papanicolaou tests.
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Adenocarcinoma/diagnóstico , Colo do Útero/patologia , Colposcopia/métodos , Neoplasias do Colo do Útero/diagnóstico , Adenocarcinoma/patologia , Adulto , Colo do Útero/citologia , Curetagem/métodos , Detecção Precoce de Câncer/métodos , Feminino , Humanos , Pessoa de Meia-Idade , Sensibilidade e Especificidade , Neoplasias do Colo do Útero/patologiaRESUMO
INTRODUCTION: Many pancreatic cystic lesions (PCL) are of neoplastic nature with potential to progress to pancreatic adenocarcinoma. Early stratification of patients to either clinical observation or surgical intervention can considerably increase the survival rate. Recent studies have shown the value of molecular analysis to current diagnostic modalities.The aim of this study is to evaluate the diagnostic improvement by utilizing multiple sequential cytologic and molecular cyst fluid analyses. MATERIALS AND METHODS: We prospectively evaluated 58 patients for whom multiple endoscopic ultrasound-guided fine-needle aspiration of cyst fluid specimens were available. Specimens were subjected to next generation sequencing to identify any recurrent gene mutations commonly found in PCL. The molecular findings were compared with cytologic and final diagnoses. RESULTS: Cytologic diagnoses were classified into 3 groups: non-diagnostic (first visit: 33.9%, cumulative: 15.8%, P = 0.03), negative (1st visit: 53.6%, cumulative: 56.1%, P = 0.85) and atypical/suspicious/positive (first visit: 12.5%, cumulative: 28.1%, P = 0.06). The mutational analyses were clustered into indeterminate/failure (first visit: 1.7%, cumulative: 0%), KRAS/GNAS/VHL group (first visit: 50.0%, cumulative: 53.4%) and any mutation (first visit: 50.0%, cumulative: 53.4%). Mutational analysis identifies up to 72% and 71% whereas cytologic analysis classified up to 46% and 63% of lesions correctly in first and multiple visits, respectively. CONCLUSIONS: The cytology and molecular analyses provide a complementary approach to patients with PCL. Power of molecular analysis in detection of a neoplastic lesion is significantly higher in one visit (P = 0.01) with comparable detection rates (P = 0.43) for both cytologic and molecular analyses after multiple visits.
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Adenocarcinoma/diagnóstico , Adenocarcinoma/genética , Cisto Pancreático/diagnóstico , Cisto Pancreático/genética , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/genética , Adenocarcinoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Líquido Cístico/química , DNA/genética , DNA/isolamento & purificação , Análise Mutacional de DNA , Aspiração por Agulha Fina Guiada por Ultrassom Endoscópico/métodos , Feminino , Seguimentos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase Multiplex , Mutação , Pâncreas/patologia , Cisto Pancreático/patologia , Neoplasias Pancreáticas/patologia , Estudos Prospectivos , Análise de Sequência de DNARESUMO
Primary peritoneal serous carcinomas (PPSC) are exceedingly rare in male patients. Only a few cases were reported, and mostly with the limited immunophenotypical characterization. No molecular analysis of PPSC in males has been previously performed. We here describe another case of PPSC in a male patient. A comprehensive molecular analysis of the tumor revealed SF3B1 gene mutation as a possible driver.
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Objectives. The rare urachal adenocarcinoma (UAC) of the bladder has striking morphologic and immunohistochemical overlap with colorectal adenocarcinoma (CAC) and bladder adenocarcinoma (BAC). To date, the mutational status in UAC and BAC has not been well investigated. Methods. We retrospectively evaluated 34 UACs (mucinous, n = 9; intestinal, n = 3; signet ring cell, n = 1; not otherwise specified, n = 21) and 4 BACs (n = 4). Next-generation sequencing analysis of 50 cancer "hotspot" gene mutations using the Ampliseq Cancer Hotspot Panel v2 was performed. Two UAC cases did not have adequate DNA quality with poor sequencing coverage and were excluded from the study. Results. RAS mutations were identified in 16 of 32 (50%) UACs (15 KRAS; 1 NRAS) and none of the BACs (0%). TP53 mutations were found in both UACs (18/32; 56%) and BACs (4/4; 100%). GNAS (n = 4), SMAD4 (n = 3), and BRAF (n = 1) mutations were only found in UACs. In contrast, APC (n = 2) mutations were only found in BACs. The mucinous subtype of UAC contained a SMAD4 mutation in 33% of cases (3/9), which was not identified in any other subtype (0/23; 0%) (P = .0169). The only BRAF mutation was identified in the single signet ring cell subtype of UAC. There were no other differences in the mutation profile when comparing histologic subtypes of UAC. Conclusions. In summary, UAC and BAC have overlapping but distinct mutation profiles and these differences may aid in separating these 2 entities. Next-generation sequencing to identify therapeutic targets or resistance markers may aid treatment decisions.
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Adenocarcinoma/genética , Biomarcadores Tumorais/genética , Sequenciamento de Nucleotídeos em Larga Escala , Mutação , Neoplasias da Bexiga Urinária/genética , Adenocarcinoma/diagnóstico , Adenocarcinoma/patologia , Adenocarcinoma/terapia , Tomada de Decisão Clínica , Diagnóstico Diferencial , Humanos , Terapia de Alvo Molecular , Estudos Retrospectivos , Neoplasias da Bexiga Urinária/diagnóstico , Neoplasias da Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/terapiaRESUMO
Objectives. Differentiating renal oncocytoma (RO) from chromophobe renal cell carcinoma (ChRCC) can occasionally be challenging. We evaluated the expression of RB1 and ERBB4 in RO and ChRCC, and compared the immunohistochemistry (IHC) results to RB1 and ERBB4 gene abnormalities detected by fluorescence in situ hybridization (FISH). Materials and Methods. Fifty-three kidney resections (ChRCC, n=28; RO, n=25) were stained for RB1 and ERBB4 IHC and FISH was performed to evaluate gene copy number analysis. Results. A loss of RB1 staining was identified in 64% (18/28) of ChRCCs, which was not found in any ROs (0/25; P <.001). FISH analysis revealed 36% (10/28) of ChRCCs contained a RB1 hemizygous deletion with a concordance of 56% (10/18) between the IHC and FISH findings. No RB1 gene copy number variations were detected in any of the ROs (0/25; P <.001) and retained expression of RB1 by IHC. ERBB4 showed cytoplasmic/membranous staining in all ROs and ChRCCs. However, 75% (21/28) of ChRCCs also contained nuclear positivity for ERBB4, which was uncommonly seen in ROs (3/25, 12%; P < .001). A hemizygous ERBB4 gene deletion was detected in 46% of ChRCCs (13/28), but none of the ROs (0/25; 0%). Loss of labeling by RB1 or nuclear staining for ERBB4 IHC identified 25 of 28 (89%) of ChRCCs. Conclusion. In summary, the loss of RB1 expression is a highly specific diagnostic biomarker in distinguishing ChRCC from RO. Nuclear ERBB4 expression also appears to be a sensitive diagnostic biomarker for ChRCC, albeit the mechanism is unknown.
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Adenoma Oxífilo/diagnóstico , Biomarcadores Tumorais/análise , Carcinoma de Células Renais/diagnóstico , Neoplasias Renais/diagnóstico , Receptor ErbB-4/biossíntese , Proteínas de Ligação a Retinoblastoma/biossíntese , Ubiquitina-Proteína Ligases/biossíntese , Diagnóstico Diferencial , Humanos , Imuno-Histoquímica , Receptor ErbB-4/análise , Proteínas de Ligação a Retinoblastoma/análise , Ubiquitina-Proteína Ligases/análiseRESUMO
The eighth edition of American Joint Committee on Cancer (AJCC) advocates a 3-tier grading system for appendiceal mucinous tumors. The mutational profile for each tumor grade and the impact of TP53 mutation on survival are unknown. We classified appendiceal mucinous tumors into 3 grades based on the eighth edition of American Joint Committee on Cancer: 21 G1 low-grade mucinous neoplasms, 21 G2 appendiceal adenocarcinomas, and 26 G3 signet ring cell carcinomas. Mutation profiles were obtained using next-generation sequencing. The impact of TP53 on prognosis was investigated by multivariable analysis. Most G1 tumors harbor KRAS/GNAS mutations with TP53 and SMAD4 in a small subset of cases. G2 and G3 tumors show a more complex mutation pattern carrying PIK3CA, BRAF, or TP53 mutations in addition to KRAS/GNAS. PTEN mutations were detected exclusively in G2 tumors. The prevalence of KRAS and GNAS mutations is significantly lower in G3 tumors relative to G1/G2, whereas TP53, PIK3CA, or BRAF mutations are common. Mutations in NRAS, IDH2, CDH1, RB1, CTNNB1, CDKN2A, PTPN11, and KIT genes were observed in single cases. Patients with TP53-mutated disseminated G2 and G3 tumors had worse progression-free survival than did those with wild-type TP53 tumors (P = .0315). A trend toward worse overall survival was observed in TP53-mutated G3 tumors (P = .102). p53 expression correlated with mutation status. We demonstrate a distinct but overlapping pattern of gene mutations in each grade of appendiceal mucinous tumors and the independent impact of TP53 mutation on progression-free survival but not overall survival.
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Adenocarcinoma Mucinoso/genética , Neoplasias do Apêndice/genética , Mutação , Proteína Supressora de Tumor p53/genética , Adenocarcinoma Mucinoso/mortalidade , Adenocarcinoma Mucinoso/patologia , Adulto , Idoso , Neoplasias do Apêndice/mortalidade , Neoplasias do Apêndice/patologia , Biomarcadores Tumorais , Classe I de Fosfatidilinositol 3-Quinases/genética , Análise Mutacional de DNA , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Prognóstico , Proteínas Proto-Oncogênicas p21(ras)/genética , Taxa de Sobrevida , beta Catenina/genéticaRESUMO
Objective: Better tools are needed for early diagnosis and classification of pancreatic cystic lesions (PCL) to trigger intervention before neoplastic precursor lesions progress to adenocarcinoma. We evaluated the capacity of molecular analysis to improve the accuracy of cytologic diagnosis for PCL with an emphasis on non-diagnostic/negative specimens. Design: In a span of 7 years, at a tertiary care hospital, 318 PCL endoscopic ultrasound-guided fine needle aspirations (EUS-FNA) were evaluated by cytologic examination and molecular analysis. Mucinous PCL were identified based on a clinical algorithm and 46 surgical resections were used to verify this approach. The mutation allele frequency (MAF) of commonly altered genes (BRAF, CDKN2A, CTNNB1, GNAS, RAS, PIK3CA, PTEN, SMAD4, TP53 and VHL) was evaluated for their ability to identify and grade mucinous PCL. Results: Cytology showed a diagnostic sensitivity of 43.5% for mucinous PCL due in part to the impact of non-diagnostic (28.8%) and negative (50.5%) specimens. Incorporating an algorithmic approach or molecular analysis markedly increased the accuracy of cytologic evaluation. Detection of mucinous PCL by molecular analysis was 93.3% based on the detection of KRAS and/or GNAS gene mutations (p = 0.0001). Additional genes provided a marginal improvement in sensitivity but were associated with cyst type (e.g. VHL) and grade (e.g. SMAD4). In the surgical cohort, molecular analysis and the proposed algorithm showed comparable sensitivity (88.9% vs. 100%). Conclusions: Incorporating somatic molecular analysis in the cytologic evaluation of EUS-FNA increases diagnostic accuracy for detection, classification and grading of PCL. This approach has the potential to improve patient management.
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OBJECTIVE: To evaluate insulin-like growth factor-II mRNA binding protein 3 (IMP3), which is an oncofetal RNA-binding protein expressed in pancreatic carcinomas and detectable by immunohistochemistry, in diagnosis of pancreatic cancer. STUDY DESIGN: We retrospectively identified 25 consecutive pancreatic endoscopic ultrasound-guided fine needle aspiration biopsies with available cell blocks, including 12 invasive pancreatic ductal carcinomas and 13 cases of chronic pancreatitis. Immunostains were performed on 4-microm tissue sections using standard techniques. Cytoplasmic staining of the lesional cells and nonneoplastic pancreatic tissue was evaluated, and the intensity of staining was recorded as absent, weak, moderate or strong. RESULTS: Eleven (92%) adenocarcinomas demonstrated staining of tumor cells with IMP3. The staining reaction was weak in 2 of 11 (18%), moderate in 5 of 11 (45%) and strong in 4 of 11 (36%) of the cases. Nonneoplastic pancreatic tissues, present in 8 of 12 carcinomas and 13 cases of chronic pancreatitis, were negative for IMP3. CONCLUSION: IMP3 is a promising new marker with high specificity and sensitivity for pancreatic adenocarcinoma.
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Biomarcadores Tumorais/análise , Biópsia por Agulha Fina , Carcinoma Ductal Pancreático/química , Carcinoma Ductal Pancreático/patologia , Proteínas de Neoplasias/análise , Neoplasias Pancreáticas/química , Neoplasias Pancreáticas/patologia , Proteínas de Ligação a RNA/análise , Idoso , Idoso de 80 Anos ou mais , Citoplasma/química , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Pancreatite Crônica/metabolismo , Pancreatite Crônica/patologia , Estudos Retrospectivos , Sensibilidade e EspecificidadeRESUMO
CONTEXT: Thyroid carcinoma is the most common malignant tumor of endocrine organs, yet it only accounts for approximately 1% of all cancers in the United States with more than 35,000 new cases diagnosed each year and more than 450,000 people living with this disease. While most tumors can be diagnosed without much difficulty, a few tumor types, especially tumors with follicular pattern, sometimes pose a diagnostic challenge. OBJECTIVE: To discuss morphologic, immunohistochemical, and molecular features of thyroid tumors. We also explore the clinicopathologic features of papillary microcarcinoma and medullary microcarcinoma and how the latter is related and differentiated from C-cell hyperplasia. Finally with the ever-growing list of organ systems involved in immunoglobulin (Ig) G4-related diseases, we discuss the still not completely explored IgG-4-related thyroid disease. DATA SOURCES: Data were obtained from review of the pertinent peer-reviewed literature and institutional experience. CONCLUSIONS: Histomorphologic evaluation still remains the gold standard for diagnosis in most cases of thyroid diseases. The application of ancillary studies such as immunohistochemistry and molecular diagnosis, including next-generation sequencing, is becoming more common.
Assuntos
Neoplasias da Glândula Tireoide/diagnóstico , Biomarcadores Tumorais/análise , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imuno-Histoquímica , Neoplasias da Glândula Tireoide/genéticaRESUMO
CONTEXT: -UroVysion fluorescent in situ hybridization (FISH) is routinely used to detect urothelial carcinoma (UC). A positive threshold is defined as chromosome polysomy in 4 or more cells, which also includes tetrasomy, a natural product of cell division. OBJECTIVES: -To evaluate tetrasomy for UC detection and explore the relation to the surgical diagnosis or patient history. DESIGN: -The FISH was performed on 1532 urine samples from patients with cytology results and 4 or more years of follow-up. We created separate polysomy and tetrasomy categories and constructed receiver operating curves to determine appropriate thresholds using biopsy (n = 194) as the gold standard. Standard FISH and a novel assay integrating cytomorphology and FISH (Target-FISH) were compared. Matching tissue biopsies of urine samples with 10 or more tetrasomy cells were analyzed. RESULTS: -No significant threshold was found for tetrasomy cells. Exclusion of tetrasomy from the polysomy category changed the threshold from 8.5 to 4.5 cells, increased specificity (59.2% to 78.9%), but reduced sensitivity (78.9% to 65.9%). In Target-FISH, the same approach yielded a specificity of 93.7% and sensitivity of 65.2%. Similarly, specificity improved significantly for low- and high-grade UC, but sensitivity decreased for low-grade UC. No evidence of UC was observed in 95% (52 of 55) of the patients referred for screening who had 10 or more tetrasomy cells by FISH. Matching biopsies for urines containing 10 or more tetrasomy cells showed few or no tetrasomy cells. CONCLUSIONS: -Tetrasomy is a nonspecific finding frequently encountered in urine FISH and should be excluded from the polysomy classification. Target-FISH is an optimal approach, offering the ability to detect rare tetrasomy tumors.