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1.
Am J Surg Pathol ; 2021 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-34469333

RESUMO

While most resection specimens from patients with neoadjuvantly treated esophageal squamous cell carcinoma show therapy-related changes in the form of inflammation and fibrosis, others harbor a florid foreign body-type giant cell response to keratin debris. The purpose of our study was to perform a detailed clinicopathologic analysis of these histologic types of treatment responses and correlate these findings with patient outcome. Clinical and pathologic parameters from 110 esophagogastrectomies were recorded and analyzed. Two main types of histologic responses were observed: inflammatory-predominant response (59%) and florid foreign body-type giant cell response to keratin (41%). Irrespective of cG, cTNM, and amount of residual cancer, florid foreign body-type giant cell reaction was predominantly noted deep within the esophageal wall, while the inflammatory response was restricted to the mucosa, submucosa, and inner half of muscularis propria. Patients with foreign body-type giant cell response showed significantly better overall survival compared with the inflammatory response group (log-rank test P=0.015). Florid foreign body-type giant cell response was the only factor associated with improved survival in a multivariable analysis for overall survival (hazard ratio=0.5; 95% confidence interval=0.3-1.0; P=0.038), but not in the model for disease-specific survival, whereas ypTNM stage II was the only significant risk factor for disease-specific survival in multivariable analysis (hazard ratio=3.4; 95% confidence interval=1.0-11.2; P=0.047). Our results suggest that in addition to the College of American Pathologists Tumor Regression Score and ypTNM stage, subtype of histologic response to therapy may represent another prognostic marker for neoadjuvantly treated esophageal squamous cell carcinoma.

2.
Nat Genet ; 53(6): 881-894, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33972779

RESUMO

Esophageal squamous cell carcinomas (ESCCs) harbor recurrent chromosome 3q amplifications that target the transcription factor SOX2. Beyond its role as an oncogene in ESCC, SOX2 acts in development of the squamous esophagus and maintenance of adult esophageal precursor cells. To compare Sox2 activity in normal and malignant tissue, we developed engineered murine esophageal organoids spanning normal esophagus to Sox2-induced squamous cell carcinoma and mapped Sox2 binding and the epigenetic and transcriptional landscape with evolution from normal to cancer. While oncogenic Sox2 largely maintains actions observed in normal tissue, Sox2 overexpression with p53 and p16 inactivation promotes chromatin remodeling and evolution of the Sox2 cistrome. With Klf5, oncogenic Sox2 acquires new binding sites and enhances activity of oncogenes such as Stat3. Moreover, oncogenic Sox2 activates endogenous retroviruses, inducing expression of double-stranded RNA and dependence on the RNA editing enzyme ADAR1. These data reveal SOX2 functions in ESCC, defining targetable vulnerabilities.


Assuntos
Adenosina Desaminase/metabolismo , Epigenoma , Neoplasias Esofágicas/genética , Carcinoma de Células Escamosas do Esôfago/genética , Proteínas de Ligação a RNA/metabolismo , Fatores de Transcrição SOXB1/metabolismo , Regiões 3' não Traduzidas/genética , Animais , Sequência de Bases , Carcinogênese/genética , Linhagem Celular Tumoral , Transformação Celular Neoplásica/genética , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Retrovirus Endógenos/genética , Elementos Facilitadores Genéticos/genética , Regulação Neoplásica da Expressão Gênica , Genoma Humano , Humanos , Interferons/metabolismo , Íntrons/genética , Fatores de Transcrição Kruppel-Like/genética , Camundongos , Organoides/patologia , Ligação Proteica , RNA de Cadeia Dupla/metabolismo , Fatores de Transcrição SOXB1/genética , Proteína Supressora de Tumor p53/metabolismo
3.
Histopathology ; 79(4): 642-649, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33960520

RESUMO

AIMS: Oesophageal verrucous carcinoma (VSCC) is a rare and morphologically distinct type of oesophageal squamous cell carcinoma (SCC). Diagnosing VSCC on biopsy material is challenging, given the lack of significant atypia and the presence of keratinising epithelium and exophytic growth. The molecular pathogenesis of VSCC remains unclear. The aim of this study was to characterise the genomic landscape of VSCC in comparison to conventional oesophageal SCC. METHODS AND RESULTS: Three cases of VSCC from the Brigham and Women's Hospital pathology archive were identified. Formalin-fixed, paraffin-embedded (FFPE) tumour tissue was used for p16 immunohistochemistry (IHC), high-risk human papillomavirus (HPV) in-situ mRNA hybridisation (ISH) and DNA isolation. Tumour DNA was sequenced using a targeted massively parallel sequencing assay enriched for cancer-associated genes. Three additional cases of VSCC were identified by image review of The Cancer Genome Atlas (TCGA) oesophageal SCC cohort. VSCC cases were negative for p16 IHC and high-risk HPV ISH. TP53 mutations (P < 0.001) and copy number variants (CNVs) for CDKN2A (P < 0.001), CDKN2B (P < 0.01) and CCND1 (P < 0.01) were absent in VSCC and significantly less frequent in comparison to conventional SCC. Five VSCC cases featured SMARCA4 missense mutations or in-frame deletions compared to only four of 88 conventional SCC cases (P < 0.001). VSCC featured driver mutations in PIK3CA, HRAS and GNAS. Recurrent CNVs were rare in VSCC. CONCLUSIONS: VSCC is not only morphologically but also genetically distinct from conventional oesophageal SCC, featuring frequent SMARCA4 mutations and infrequent TP53 mutations or CDKN2A/B CNVs. Molecular findings may aid in establishing the challenging diagnosis of VSCC.

4.
Ann Diagn Pathol ; 51: 151672, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33418428

RESUMO

Subsquamous intestinal metaplasia (SSIM) in the setting of Barrett's esophagus (BE) is a technically challenging diagnosis. While the risk for progression of BE involving the surface mucosa is well documented, the potential risk for development of advanced neoplasia associated with SSIM has been controversial. This study aimed to determine the effects of specimen adequacy, presence of dysplasia, and interobserver agreement for SSIM interpretation. Adult patients (n = 28) who underwent endoscopic therapy for BE with high-grade dysplasia or intramucosal carcinoma (HGD/IMC) between October 2005 and June 2013 were included. Initial evaluation (n = 140 slides) by an experienced gastrointestinal pathologist was followed by an interobserver study by 8 pathologists. Forty-seven (34%) slides had insufficient subsquamous tissue to assess for SSIM. SSIM was found in 19% of all slides and 29% of slides with sufficient subsquamous tissue. At least one slide had SSIM in 54% to 64% of patients. Subsquamous low grade dysplasia (LGD) was found in 4 (15%) slides with SSIM and subsquamous HGD/IMC was found in 5 (19%) slides with SSIM. At the patient level, 8 (53%) had no dysplasia, 4 (27%) had LGD and 3 (20%) had HGD/IMC. Overall agreement for SSIM by slide was 92% to 94% (κ = 0.73 to κ = 0.82, moderate to strong agreement), and by patient was 82% to 94% (κ = 0.65 to κ = 0.87, moderate to strong agreement). This study confirms the need for assessing specimen adequacy and assessing the prevalence of SSIM and is the first to assess interobserver agreement for SSIM and dysplasia within SSIM.

7.
Am J Surg Pathol ; 44(5): 617-625, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32187043

RESUMO

Common variable immunodeficiency (CVID) has a heterogenous clinical presentation and can be challenging to diagnose. Distinct histologic changes have been linked with CVID in several organ systems, which can help identify the correct diagnosis. In this study we review a cohort of hepatic CVID biopsies, to better define the spectrum of histologic and biochemical alterations. We reviewed 26 liver biopsies from 24 patients with CVID, obtained at 4 institutions between 2010 and 2019. Histologic slides were examined, and pathologic, biochemical, and clinical features were recorded. A control cohort of 21 patients with nodular regenerative hyperplasia (NRH) but lacking CVID was also examined. Liver function tests were frequently abnormal, especially alkaline phosphatase (median: 193 IU/L) and aspartate transaminase (median: 56 U/L), elevated in 23 and 17 of 25 biopsies, respectively. Fifteen patients had CVID involvement of other organs. Histologic features of primary biliary cholangitis were present in 2 patients, with florid duct lesions and prominent bile duct injury, in association with positive antimitochondrial antibodies. Among the other 24 biopsies, mild to moderate portal and lobular inflammation were present in 18 and 17 of 24 biopsies, respectively. Overall, 22 of 24 biopsies showed NRH-like changes. Plasma cell were absent. A distinct pattern of pericellular fibrosis was present in 23 of 26 biopsies overall. Involvement ranged from focal centrizonal fibrosis to bridging fibrosis and was accompanied by increased intrasinusoidal lymphocytes in 13 of 24 biopsies. Pericellular fibrosis was identified in 1 of 21 biopsies in the control cohort. Additional findings included granulomatous inflammation or nonhepatocellular foreign body-type multinucleate giant cells, identified in 4 biopsies. Three of 6 examined biopsies also demonstrated focal hepatocellular copper deposition. Hepatic disease in CVID is often associated with elevated alkaline phosphatase and aspartate transaminase and is characterized histologically by the mild nonspecific portal and lobular hepatitis, absence of plasma cells, NRH-like changes, and less commonly, typical histologic features of primary biliary cholangitis. We have also identified a distinctive pattern of delicate pericellular fibrosis that is a helpful clue to the diagnosis of hepatic disease in CVID, especially when accompanied by NRH-like changes.


Assuntos
Imunodeficiência de Variável Comum/complicações , Hepatite/etiologia , Hipertensão Portal/etiologia , Cirrose Hepática/etiologia , Fígado/patologia , Adolescente , Adulto , Idoso , Biomarcadores/sangue , Biópsia , Estudos de Casos e Controles , Imunodeficiência de Variável Comum/diagnóstico , Imunodeficiência de Variável Comum/imunologia , Feminino , Hepatite/imunologia , Hepatite/patologia , Humanos , Hipertensão Portal/imunologia , Hipertensão Portal/patologia , Fígado/imunologia , Cirrose Hepática/imunologia , Cirrose Hepática/patologia , Testes de Função Hepática , Masculino , Pessoa de Meia-Idade , Plasmócitos/imunologia , Plasmócitos/patologia , Valor Preditivo dos Testes , Turquia , Estados Unidos , Adulto Jovem
8.
Gastroenterology Res ; 13(1): 32-39, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32095171

RESUMO

Background: Phlebotomy induces regression of liver fibrosis in genetic hemochromatosis. We assessed the histologic changes in pre-phlebotomy and post-phlebotomy liver biopsies from patients with HFE mutation as a model to study regression of fibrosis. We aimed to show that phlebotomy-induced histologic lesions overlap with porto-sinusoidal vascular disease (PSVD, also known as idiopathic non-cirrhotic portal hypertension), histologically. Methods: A total of 51 biopsies (22 pre-phlebotomy and 29 post-phlebotomy) were reviewed, and three variables were studied: iron index indicative of the amount of accumulated iron (range 0 to 18), the combined score of vascular changes reflecting the presence of histological lesions that are described in PSVD (range 0 to 9) and the high-grade shunt vessel by calculating the proportion of portal tracts with shunt vessels, with a cutoff of 50%. Two-tailed Student's t-test and Fisher's exact test were performed to compare the means of two variables and frequencies of the histologic lesions in two groups, respectively. A P-value < 0.05 was considered statistically significant. Results: The iron index was higher in the pre-phlebotomy compared to post-phlebotomy group (P = 0.01). Compared to the pre-phlebotomy group, the combined score was higher in the post-phlebotomy group when the cases of advanced fibrosis were excluded (P = 0.023) and remained higher when patients with risk factors for PSVD were further excluded (P = 0.034). The high-grade shunt vessel tended to be more common in the post-phlebotomy group when advanced fibrosis was excluded; however, the statistical significance was marginal (P = 0.056). Conclusions: Phlebotomy reduces hepatic iron load and induces histologic lesions of PSVD in patients with HFE mutation. Our data support a postulation that some of the histologic lesions of PSVD represent vascular remodeling following a regression of fibrosis and may not be reflective of risk factors or etiopathogenesis of PSVD. Regressed fibrosis and PSVD may not be reliably distinguished in a limited sample, therefore warranting cautious interpretation in the right clinical context.

9.
Adv Anat Pathol ; 27(3): 193-205, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-30234501

RESUMO

As in other organ systems, immunohistochemistry (IHC) serves as an ancillary diagnostic tool for a wide variety of neoplastic and non-neoplastic disorders, including infections, work-up of inflammatory conditions, and subtyping neoplasms of the gastrointestinal (GI) tract. In addition, IHC is also used to detect a variety of prognostic and predictive molecular biomarkers for carcinomas of the GI tract. The purpose of this review is to highlight the use of IHC in common diagnostic scenarios throughout the tubular GI tract. The clinical indication and guidelines for performing IHC for detecting Helicobacter pylori is discussed along with role of gastrin and neuroendocrine markers in the diagnosis of autoimmune metaplastic atrophic gastritis. The major portion of this review discusses the use of IHC in the diagnostic workup of malignant neoplasms of the GI tract, such as adenocarcinoma versus squamous cell carcinoma, workup of poorly differentiated malignant neoplasms, and evaluation of uncommon gastric neoplasms (alpha-feto protein-producing carcinomas) and switch/sucrose-nonfermenting complex-deficient carcinomas. Lastly, localization of neuroendocrine tumors of unknown origin to aid clinical management, as well as HPV-driven anal neoplasia and IHC in the workup of basaloid anal neoplasms are also reviewed.


Assuntos
Gastroenteropatias/diagnóstico , Imuno-Histoquímica/métodos , Biomarcadores/análise , Diagnóstico Diferencial , Humanos
10.
Clin Cancer Res ; 26(6): 1277-1287, 2020 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-31852835

RESUMO

PURPOSE: Sessile serrated lesions (SSL) are precursors to colon carcinoma, and their distinction from other polyps, in particular hyperplastic polyps (HP), presents significant diagnostic challenges. We evaluated expression patterns in colonic polyps of previously identified colon carcinoma-associated extracellular matrix (ECM) proteins to identify markers distinguishing SSLs from other polyps. EXPERIMENTAL DESIGN: Gene-expression analyses of ECM proteins were performed using publicly available data on preneoplastic colonic polyps. In parallel, we evaluated by IHC the expression of agrin (AGRN) in over 400 colonic polyps, including HP, SSL with and without dysplasia, traditional serrated adenomas (TSA), and tubular adenomas (TA), and compared the consistency of standard histologic diagnosis of SSLs by experienced gastrointestinal pathologists with that of AGRN IHC. RESULTS: Differential gene expression analysis and IHC identified AGRN, serine peptidase inhibitor (SERPINE2), and TIMP metallopeptidase inhibitor 1 (TIMP1) elevated in SSLs and HPs but decreased in TAs and absent in normal colon. AGRN-positive basal laminae were noted in all TA, TSA, HP, and SSL in distinguishable patterns, whereas other polyps and normal mucosa were negative. SSL with or without dysplasia consistently showed IHC staining for AGRN in the muscularis mucosae, which was absent in HP, TSA, TA, and other polyps. In contrast, histologic evaluation showed only weak interobserver agreement (kappa value = 0.493) in distinguishing SSLs. CONCLUSIONS: Muscularis mucosae-based AGRN immunostaining is a novel biomarker to distinguish SSL from HP, TSA, and TA, with a specificity of 97.1% and sensitivity of 98.9% and can assist in diagnosis of morphologically challenging colonic polyps.


Assuntos
Agrina/metabolismo , Biomarcadores Tumorais/metabolismo , Pólipos do Colo/diagnóstico , Neoplasias Colorretais/diagnóstico , Regulação Neoplásica da Expressão Gênica , Hiperplasia/diagnóstico , Membrana Mucosa/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Agrina/genética , Criança , Pré-Escolar , Pólipos do Colo/genética , Pólipos do Colo/metabolismo , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Diagnóstico Diferencial , Humanos , Hiperplasia/genética , Hiperplasia/metabolismo , Pessoa de Meia-Idade , Membrana Mucosa/patologia , Adulto Jovem
11.
Am J Surg Pathol ; 44(1): 77-86, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31403964

RESUMO

Metastatic invasive lobular carcinoma (mILC) may masquerade as primary diffuse gastric adenocarcinoma (PDGA) by demonstrating significant clinical and pathologic overlap. Accurate distinction is of therapeutic and prognostic significance. On the basis of anecdotal cases of mILC that lacked estrogen receptor and/or GATA3 expression, we analyzed the cytoarchitectural features of 28 mILC and 44 PDGA specimens obtained from women to assess features that would help in this distinction and prompt ancillary work-up. In addition to performing an interobserver agreement analysis among 3 pathologists, we also evaluated SATB2 expression in this setting. Eighteen of 20 (90%) patients had a history of ILC. The mean interval between initial diagnosis of breast cancer and metastasis was 7.3 years (range: 1 to 36 y). Compared with mILC, PDGA was significantly associated with full-thickness mucosal involvement (47% vs. 80%; P=0.015), a nested/sheet-like growth pattern (32% vs. 68%; P=0.004), anastomosing cords (0% vs. 100%; P=0.001), multivacuolated cells (0% vs. 61%; P<0.0001), pleomorphic nuclei (4% vs. 70%; P<0.0001) and enlarged nuclei (4% vs. 70%; P<0.0001). Single file growth pattern (P<0.0001) and superficial lamina propria involvement (P=0.009) were more common in mILC. Estrogen receptor and GATA3 were expressed in all but 5 mILC cases; SATB2 was only seen in 30% of PDGA cases. Our results demonstrate that in a biopsy specimen, careful morphologic assessment can be extremely helpful in distinguishing mILC from PDGA and guiding ancillary work-up, especially when a history of breast cancer may not be readily available or when the neoplasm lacks expression of conventional breast markers.


Assuntos
Adenocarcinoma/patologia , Neoplasias da Mama/patologia , Carcinoma Lobular/patologia , Neoplasias Gástricas/patologia , Adenocarcinoma/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/metabolismo , Carcinoma Lobular/metabolismo , Carcinoma Lobular/secundário , Diagnóstico Diferencial , Feminino , Fator de Transcrição GATA3/biossíntese , Humanos , Pessoa de Meia-Idade , Receptores de Estrogênio/biossíntese , Estudos Retrospectivos , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/secundário
12.
Clin Transl Gastroenterol ; 12(1): e00272, 2020 12 22.
Artigo em Inglês | MEDLINE | ID: mdl-33464729

RESUMO

INTRODUCTION: The expression of LGR5, a known stem cell marker, is poorly understood in Barrett's esophagus (BE) and related neoplasia. The aim of this study was to evaluate LGR5 in BE and related neoplasia and to evaluate its utility as a potential biomarker of progression to advanced neoplasia. METHODS: We evaluated total 137 patients, including 119 with BE and 18 with normal gastroesophageal mucosa for expression of LGR5 using RNA in situ hybridization; this also included 28 progressors and 30 nonprogressors. The LGR5 stain was evaluated using 1 qualitative and 2 quantitative parameters, using manual and automated platforms. RESULTS: Surface LGR5 expression was mainly seen in high-grade dysplasia (12/18) compared with low-grade dysplasia (1/8) and nondysplastic BE (0/17) (P < 0.0001). In contrast to nondysplastic BE, low- and high-grade dysplasia showed a higher percentage of mean number of LGR5-positive crypts per patient (P < 0.0001) and an increase in the mean number of LGR5 transcripts per cell (P < 0.0001). The mean percentage of LGR5-positive crypts per patient and the mean number of LGR5 transcripts per cell were also significantly higher in nondysplastic BE from progressor compared with nonprogressor (P < 0.0001, P = 0.014). The sensitivity and specificity of LGR5 for distinguishing progressor from nonprogressor were 50% and 87%, respectively. DISCUSSION: BE-related advanced neoplasia shows an expansion of the LGR5-positive cellular compartment, supporting its role as a stem cell marker in this disease. Quantitative LGR5 expression and surface epithelial reactivity are novel biomarkers of increased risk of progression to advanced neoplasia in BE.


Assuntos
Adenocarcinoma/epidemiologia , Esôfago de Barrett/patologia , Biomarcadores Tumorais/análise , Neoplasias Esofágicas/epidemiologia , Receptores Acoplados a Proteínas G/análise , Adenocarcinoma/diagnóstico , Adenocarcinoma/genética , Adenocarcinoma/patologia , Adulto , Idoso , Esôfago de Barrett/genética , Biomarcadores Tumorais/genética , Biópsia , Progressão da Doença , Mucosa Esofágica/diagnóstico por imagem , Mucosa Esofágica/patologia , Neoplasias Esofágicas/diagnóstico , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patologia , Esofagoscopia , Feminino , Seguimentos , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Valor Preditivo dos Testes , Receptores Acoplados a Proteínas G/genética , Estudos Retrospectivos , Medição de Risco/métodos
13.
Appl Immunohistochem Mol Morphol ; 27(6): 454-460, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-29561272

RESUMO

Although nuclear immunostaining for paired box protein (PAX5) is widely used in practice, its cytoplasmic localization has not been evaluated. Recently we encountered cytoplasmic granular PAX5 staining in rectal well-differentiated neuroendocrine tumor (WD-NET) in the absence of nuclear staining. We investigated the specificity of this staining pattern for rectal NET (n=21) in comparison with 108 NETs, 1 WD rectal NET with elevated proliferation (WD-NET G3), and 40 poorly differentiated neuroendocrine carcinomas from the gastrointestinal and pancreatobiliary tract and liver. Representative tumor sections were subject to immunohistochemical stain for PAX5 antibody. Immunohistochemistry for 3 L-cell markers, glucagon-like peptide 1 and 2, and peptide YY, was performed on all rectal and appendiceal NETs and all other NETs with cytoplasmic PAX5 staining. Cytoplasmic PAX5 staining was observed in 90% (19/21) of rectal NET, 27% (3/11) of appendiceal, 14% (2/14) of pancreatic, 7% (2/29) of lung, 25% (3/12) metastatic NET in the liver, and 100% (1/1) of renal NET. No PAX5 cytoplasmic staining was seen in all grades of NET in other organs, rectal WD-NET G3, and all neuroendocrine carcinoma. L-cell marker staining was observed in all 21 (100%) rectal, in 3 of 3 (100%) PAX5-positive, and 1 of 7 (14%) PAX5-negative appendiceal NET. Cytoplasmic PAX5 staining is specific for rectal carcinoids. The sensitivity and specificity of PAX5 to detect L-cell type rectal carcinoids is 90% (19/21) and 100% (21/21), respectively. Cytoplasmic localization of the PAX5 protein may be utilized as a surrogate marker to detect L-cell type rectal carcinoids.


Assuntos
Biomarcadores Tumorais/metabolismo , Citoplasma/metabolismo , Tumores Neuroendócrinos/metabolismo , Fator de Transcrição PAX5/metabolismo , Neoplasias Retais/metabolismo , Adolescente , Adulto , Diferenciação Celular , Criança , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Tumores Neuroendócrinos/diagnóstico , Valor Preditivo dos Testes , Prognóstico , Neoplasias Retais/diagnóstico , Sensibilidade e Especificidade , Adulto Jovem
14.
Ann Diagn Pathol ; 37: 30-34, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30236546

RESUMO

BACKGROUND: The expression profile of immunohistochemical markers of origin in poorly differentiated neuroendocrine carcinoma (PDNEC) is not well studied. MATERIALS AND METHODS: Seventy-four PDNECs from gastroenteropancreatic (GEP) organs and the lung, including 48 large cell NEC (LCNEC) and 26 small cell carcinomas (SmCC), were subject to immunohistochemical staining for CDX2, TTF1 and ISL1. The staining intensity (1 to 3) and percentage of positive tumor cells [0 (negative), 1 (<50%) and 2 (≥50%)] were assessed. The multiplicative index (maximum 6) was calculated and the average total score (aTS) was determined for each primary site and histologic subtype. RESULTS: In the 38 GEP and 36 lung PDNECs, CDX2, TTF1 and ISL1 staining was observed in 71% (aTS 2.8), 16% (aTS 0.4), 63% (aTS 1.9), and 22% (aTS 0.6), 72% (aTS 2.9) and 92% (aTS 3.8), respectively. GEP PDNECs showed a higher aTS for CDX2 and lower aTS for TTF1 and ISL1, compared to that of lung PDNECs (Student's t-test, p < 0.001). SmCC had a higher aTS for TTF1 and ISL1 (p < 0.001) and lower aTS for CDX2 (p < 0.002) than that of LCNEC. CONCLUSIONS: CDX2 and TTF1 demonstrate potential utility in suggesting the primary site of PDNEC. In addition, CDX2 may be useful in supporting the diagnosis of LCNEC in cases with overlapping or borderline morphology. Utility of ISL1 as an adjunctive diagnostic marker of SmCC remains to be studied.


Assuntos
Biomarcadores Tumorais/análise , Fator de Transcrição CDX2/biossíntese , Carcinoma Neuroendócrino/diagnóstico , Proteínas de Ligação a DNA/biossíntese , Proteínas com Homeodomínio LIM/biossíntese , Fatores de Transcrição/biossíntese , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Neuroendócrino/patologia , Feminino , Humanos , Neoplasias Intestinais/diagnóstico , Neoplasias Intestinais/patologia , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Tumores Neuroendócrinos/diagnóstico , Tumores Neuroendócrinos/patologia , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/patologia , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/patologia
16.
Ann N Y Acad Sci ; 1434(1): 185-191, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-29797752

RESUMO

Lymphocytic esophagitis is a histologic pattern of injury characterized by increased intraepithelial lymphocytes (>20/high-power field) with rare, or absent granulocytes. Lymphocytes tend to be more numerous in the peripapillary epithelium, and are often associated with evidence of mucosal injury, edema, and scattered dyskeratotic cells. More than a decade following its original description, lymphocytic esophagitis remains an enigmatic entity with variable clinical presentations, associated disorders, etiologies, treatment, and natural history. Most of the confusion regarding the clinical significance of this disorder stems from its diagnostic criteria: lymphocytic esophagitis is currently defined based entirely on histologic criteria, despite the common occurrence of lymphocytosis in a variety of unrelated inflammatory conditions of the esophagus. The goal of this review is to summarize the literature regarding lymphocytic esophagitis and focus on key clinicopathologic features that distinguish it from other esophageal disorders that can show increased numbers of intraepithelial lymphocytes.


Assuntos
Esofagite , Esofagoscopia , Esôfago , Linfócitos/imunologia , Linfocitose , Esofagite/diagnóstico , Esofagite/imunologia , Esofagite/fisiopatologia , Esofagite/terapia , Esôfago/imunologia , Esôfago/fisiopatologia , Humanos , Linfocitose/diagnóstico , Linfocitose/imunologia , Linfocitose/fisiopatologia , Linfocitose/terapia
17.
Hum Pathol ; 78: 131-137, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29698701

RESUMO

Mucinous variant of intrahepatic cholangiocarcinoma (iCC) is rare, and its clinicopathological features and prognosis are far less clear. Six patients who had iCCs with more than 50% of mucinous component and 79 conventional iCCs were included in the study. The mean size of mucinous and conventional iCCs was 6.2 and 6.0 cm, respectively. Most patients (83%) with mucinous iCC presented at T3 stage or above compared with 28% of the conventional group (P < .01). Three patients with mucinous iCC (50%) died within 1 year. The average survival time of patients with mucinous iCCs was significantly reduced compared with that of the conventional group (9 months versus 2 years; P < .001). Immunohistochemistry was performed on 6 mucinous and 12 conventional iCCs with matched age, sex, and stage, which revealed positive immunoreactivity in MUC1 (83% versus 58%), MUC2 (33% versus 17%), MUC5AC (100% versus 42%), MUC6 (50% versus 0), CK7 (83% versus 83%), CK20 (0 versus 17%), CDX2 (17% versus 0), p53 (67% versus 67%), Smad4 (67% versus 58%), and EGFR (83% versus 42%) in mucinous and conventional iCCs, respectively. Molecular studies showed one mucinous iCC with KRAS G12C mutation and no BRAF or IDH1/2 mutations. Mucinous iCC is a unique variant that constitutes 7% of iCCs. It is more immunoreactive for MUC1, MUC2, MUC5AC, and MUC6. Unlike adenocarcinomas of colorectal primary, mucinous iCCs are often CK7+/CK20-/CDX2- and microsatellite stable. Patients with mucinous iCC likely present at advanced stage upon diagnosis with shorter survival time compared with the conventional counterparts.


Assuntos
Adenocarcinoma Mucinoso/patologia , Neoplasias dos Ductos Biliares/patologia , Colangiocarcinoma/patologia , Neoplasias Hepáticas/patologia , Adenocarcinoma Mucinoso/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias dos Ductos Biliares/diagnóstico , Biomarcadores Tumorais , Colangiocarcinoma/diagnóstico , Feminino , Humanos , Imuno-Histoquímica/métodos , Neoplasias Hepáticas/diagnóstico , Masculino , Pessoa de Meia-Idade , Prognóstico
18.
Arch Pathol Lab Med ; 142(5): 645-661, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29480761

RESUMO

Context The Staging and Prognostic Factors Committee of the International Association for the Study of Lung Cancer, in conjunction with the International Mesothelioma Interest Group, the International Thymic Malignancy Interest Group, and the Worldwide Esophageal Cancer Collaboration, developed proposals for the 8th edition of their respective tumor, node, metastasis (TNM) staging classification systems. Objective To review these changes and discuss issues for the reporting pathologist. Data Sources Proposals were based on international databases of lung (N = 94 708), with an external validation using the US National Cancer Database; mesothelioma (N = 3519); thymic epithelial tumors (10 808); and epithelial cancers of the esophagus and esophagogastric junction (N = 22 654). Conclusions These proposals have been mostly accepted by the Union for International Cancer Control and the American Joint Committee on Cancer and incorporated into their respective staging manuals (2017). The Union for International Cancer Control recommended implementation beginning in January 2017; however, the American Joint Committee on Cancer has deferred deployment of the eighth TNM until January 1, 2018, to ensure appropriate infrastructure for data collection. This manuscript summarizes the updated staging of thoracic malignancies, specifically highlighting changes from the 7th edition that are relevant to pathologic staging. Histopathologists should become familiar with, and start to incorporate, the 8th edition staging in their daily reporting of thoracic cancers henceforth.


Assuntos
Estadiamento de Neoplasias/métodos , Neoplasias Torácicas/patologia , Humanos
19.
Virchows Arch ; 472(1): 67-80, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29177895

RESUMO

Certain types of colitides, such as collagenous colitis, lymphocytic colitis, and ischemic colitis, have distinct histologic features that allow for a specific diagnosis. However, in most colonic biopsy specimens, a definite diagnosis cannot be established on the basis of histology alone. Thus, in most cases of colitis, it is helpful to utilize a systematic approach in order to recognize patterns of injury. This information in conjunction with clinical and laboratory findings may help pathologists narrow the differential diagnosis and/or establish a more definite etiology for the patient's illness in order to guide clinical management. We provide general guidelines to distinguish variations in normal mucosa and biopsy procedure-related artifacts from true inflammatory conditions. Inflammatory conditions may be further categorized into those with predominantly lymphoplasmacytic inflammation (with or without neutrophils), predominantly neutrophilic inflammation, predominantly eosinophilic inflammation, or paucicellular colitis, since each of these patterns of inflammation are associated with a distinct differential diagnosis. This review will focus on a pattern-based algorithmic approach to evaluating biopsies of patients who present to physicians with signs and symptoms of colitis.


Assuntos
Algoritmos , Colite/diagnóstico , Biópsia , Humanos
20.
Am J Surg Pathol ; 42(1): 39-52, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28961557

RESUMO

Most prior studies of primary diagnosis in surgical pathology using whole slide imaging (WSI) versus microscopy have focused on specific organ systems or included relatively few cases. The objective of this study was to demonstrate that WSI is noninferior to microscopy for primary diagnosis in surgical pathology. A blinded randomized noninferiority study was conducted across the entire range of surgical pathology cases (biopsies and resections, including hematoxylin and eosin, immunohistochemistry, and special stains) from 4 institutions using the original sign-out diagnosis (baseline diagnosis) as the reference standard. Cases were scanned, converted to WSI and randomized. Sixteen pathologists interpreted cases by microscopy or WSI, followed by a wash-out period of ≥4 weeks, after which cases were read by the same observers using the other modality. Major discordances were identified by an adjudication panel, and the differences between major discordance rates for both microscopy (against the reference standard) and WSI (against the reference standard) were calculated. A total of 1992 cases were included, resulting in 15,925 reads. The major discordance rate with the reference standard diagnosis was 4.9% for WSI and 4.6% for microscopy. The difference between major discordance rates for microscopy and WSI was 0.4% (95% confidence interval, -0.30% to 1.01%). The difference in major discordance rates for WSI and microscopy was highest in endocrine pathology (1.8%), neoplastic kidney pathology (1.5%), urinary bladder pathology (1.3%), and gynecologic pathology (1.2%). Detailed analysis of these cases revealed no instances where interpretation by WSI was consistently inaccurate compared with microscopy for multiple observers. We conclude that WSI is noninferior to microscopy for primary diagnosis in surgical pathology, including biopsies and resections stained with hematoxylin and eosin, immunohistochemistry and special stains. This conclusion is valid across a wide variety of organ systems and specimen types.


Assuntos
Técnicas de Preparação Histocitológica/métodos , Patologia Cirúrgica/métodos , Humanos , Microscopia , Variações Dependentes do Observador , Reprodutibilidade dos Testes , Método Simples-Cego
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