RESUMEN
With the development of chest CT screening, surgically resected lung tumors have shifted from predominantly large masses to predominantly small nodules. The intraoperative frozen diagnosis of pulmonary small nodules faces many challenges, such as the accurate understanding about the concepts of adenocarcinoma in situ, minimally invasive adenocarcinoma and lepidic adenocarcinoma, as well as their differential diagnosis with small size invasive adenocarcinoma, benign tumors (such as bronchiolar adenoma, sclerosing pneumocytoma, etc.), metastatic tumors and so on. This study summarizes some common problems encountered in the intraoperative frozen diagnosis of small pulmonary nodules in daily practice, focusing on the diagnosis and differential diagnosis of adenocarcinoma, in order to make the accurate intraoperative frozen diagnosis of small pulmonary nodules and diminish misdiagnosis.
Asunto(s)
Adenocarcinoma , Secciones por Congelación , Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/diagnóstico por imagen , Neoplasias Pulmonares/cirugía , Diagnóstico Diferencial , Adenocarcinoma/patología , Adenocarcinoma/diagnóstico , Adenocarcinoma/cirugía , Nódulo Pulmonar Solitario/patología , Nódulo Pulmonar Solitario/diagnóstico por imagen , Nódulo Pulmonar Solitario/diagnóstico , Nódulos Pulmonares Múltiples/patología , Nódulos Pulmonares Múltiples/diagnóstico por imagen , Nódulos Pulmonares Múltiples/cirugía , Nódulos Pulmonares Múltiples/diagnóstico , Adenocarcinoma in Situ/patología , Adenocarcinoma in Situ/diagnóstico , Adenocarcinoma in Situ/cirugía , Periodo IntraoperatorioRESUMEN
OBJECTIVE: The genomic and molecular ecology involved in the stepwise continuum progression of lung adenocarcinoma (LUAD) from adenocarcinoma in situ (AIS) to minimally invasive adenocarcinoma (MIA) and subsequent invasive adenocarcinoma (IAC) remains unclear and requires further elucidation. We aimed to characterize gene mutations and expression landscapes, and explore the association between differentially expressed genes (DEGs) and significantly mutated genes (SMGs) during the dynamic evolution from AIS to IAC. METHODS: Thirty-five patients with ground-glass nodules (GGNs) lung adenocarcinomas were enrolled. Whole-exome sequencing (WES) and transcriptome sequencing (RNA-Seq) were conducted on all patients, encompassing both tumor samples and corresponding noncancerous tissues. Data obtained from WES and RNA-Seq were subsequently analyzed. RESULTS: The findings from WES delineated that the predominant mutations were observed in EGFR (49%) and ANKRD36C (17%). SMGs, including EGFR and RBM10, were associated with the dynamic evolution from AIS to IAC. Meanwhile, DEGs, including GPR143, CCR9, ADAMTS16, and others were associated with the entire process of invasive LUAD. We found that the signaling pathways related to cell migration and invasion were upregulated, and the signaling pathways of angiogenesis were downregulated across the pathological stages. Furthermore, we found that the messenger RNA (mRNA) levels of FAM83A, MAL2, DEPTOR, and others were significantly correlated with CNVs. Gene set enrichment analysis (GSEA) showed that heme metabolism and cholesterol homeostasis pathways were significantly upregulated in patients with EGFR/RBM10 co-mutations, and these patients may have poorer overall survival than those with EGFR mutations. Based on the six calculation methods for the immune infiltration score, NK/CD8+ T cells decreased, and Treg/B cells increased with the progression of early LUAD. CONCLUSIONS: Our findings offer valuable insights into the unique genomic and molecular features of LUAD, facilitating the identification and advancement of precision medicine strategies targeting the invasive progression of LUAD from AIS to IAC.
Asunto(s)
Adenocarcinoma del Pulmón , Secuenciación del Exoma , Neoplasias Pulmonares , Mutación , Invasividad Neoplásica , Humanos , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/patología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Masculino , Femenino , Persona de Mediana Edad , Anciano , Progresión de la Enfermedad , Regulación Neoplásica de la Expresión Génica , Transcriptoma , Perfilación de la Expresión Génica , Adenocarcinoma in Situ/genética , Adenocarcinoma in Situ/patología , Lesiones Precancerosas/genética , Lesiones Precancerosas/patología , Biomarcadores de Tumor/genéticaRESUMEN
OBJECTIVE: Hysterectomy has been the historical gold standard final step in the treatment algorithm of adenocarcinoma in situ (AIS) recommended by most North American colposcopy guidelines. AIS disproportionately affects young childbearing age women, therefore a fertility sparing treatment option is desirable. Our study examines the impact of conservative treatment of AIS with conization followed by serial surveillance. METHODS: A retrospective chart review was completed of patients treated for AIS from 2006 to 2020. Charts were identified by pathologic diagnosis of AIS on cervical and uterine specimens. Charts were excluded if AIS was not treated with conization, if AIS was not confirmed on initial conization specimen, or if invasive disease was found at initial conization. RESULTS: 121 patient charts were analyzed. Median age of patients at first conization and hysterectomy was 34.8 and 40.9, respectively. First conization was by Cold Knife Cone in 58% of patients, and by Loop Electrosurgical Excisional Procedure in 42% of patients. Median follow-up period in our study was 609 days. 5% of patients had recurrence, with only one patient who recurred as cancer. One case of recurrence had a positive initial conization margin. Median time to recurrence was 700 days. 47% of patients underwent eventual hysterectomy. Residual AIS was found in 23% of hysterectomy specimens. Adenocarcinoma was diagnosed on hysterectomy specimen in four patients. CONCLUSION: Our study demonstrates the oncologic safety of treating AIS with conization and serial surveillance. Routine hysterectomy completed as a part of the AIS treatment algorithm, as in current clinical guidelines, is unnecessary.
Asunto(s)
Adenocarcinoma in Situ , Conización , Histerectomía , Neoplasias del Cuello Uterino , Humanos , Femenino , Conización/métodos , Neoplasias del Cuello Uterino/cirugía , Neoplasias del Cuello Uterino/patología , Estudios Retrospectivos , Adulto , Adenocarcinoma in Situ/cirugía , Adenocarcinoma in Situ/patología , Histerectomía/métodos , Histerectomía/estadística & datos numéricos , Estudios de Seguimiento , Persona de Mediana Edad , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/epidemiología , Preservación de la Fertilidad/métodos , Adulto JovenAsunto(s)
Neoplasias del Recto , Procedimientos Quirúrgicos Robotizados , Cirugía Endoscópica Transanal , Humanos , Procedimientos Quirúrgicos Robotizados/métodos , Neoplasias del Recto/cirugía , Cirugía Endoscópica Transanal/métodos , Cirugía Endoscópica Transanal/instrumentación , Adenocarcinoma in Situ/cirugía , Adenocarcinoma in Situ/patología , Masculino , Femenino , Adenocarcinoma/cirugíaRESUMEN
BACKGROUND: Adenocarcinomas show a stepwise progression from atypical adenomatous hyperplasia (AAH) through adenocarcinoma in situ (AIS) to invasive adenocarcinoma (IA). Immunoglobulin superfamily containing leucine-rich repeat (ISLR) is a marker of tumor-restraining cancer-associated fibroblasts (CAFs), which are distinct from conventional, strongly α-smooth muscle actin (αSMA)-positive CAFs. Fibroblast activation protein (FAP) has been focused on as a potential therapeutic and diagnostic target of CAFs. METHODS: We investigated the changes in protein expression during adenocarcinoma progression in the pre-existing alveolar septa by assessing ISLR, αSMA, and FAP expression in normal lung, AAH, AIS, and IA. Fourteen AAH, seventeen AIS, and twenty IA lesions were identified and randomly sampled. Immunohistochemical analysis was performed to evaluate cancer-associated changes and FAP expression in the pre-existing alveolar structures. RESULTS: Normal alveolar septa expressed ISLR. The ISLR level in the alveolar septa decreased in AAH and AIS tissues when compared with that in normal lung tissue. The αSMA-positive area gradually increased from the adjacent lung tissue (13.3% ± 15%) to AIS (87.7% ± 14%), through AAH (70.2% ± 21%). Moreover, the FAP-positive area gradually increased from AAH (1.69% ± 1.4%) to IA (11.8% ± 7.1%), through AIS (6.11% ± 5.3%). Protein expression changes are a feature of CAFs in the pre-existing alveolar septa that begin in AAH. These changes gradually progressed from AAH to IA through AIS. CONCLUSIONS: FAP-positive fibroblasts may contribute to tumor stroma formation in early-stage lung adenocarcinoma, and this could influence the development of therapeutic strategies targeting FAP-positive CAFs for disrupting extracellular matrix formation.
Asunto(s)
Adenocarcinoma del Pulmón , Progresión de la Enfermedad , Endopeptidasas , Neoplasias Pulmonares , Proteínas de la Membrana , Humanos , Adenocarcinoma del Pulmón/patología , Adenocarcinoma del Pulmón/metabolismo , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/metabolismo , Masculino , Femenino , Persona de Mediana Edad , Proteínas de la Membrana/metabolismo , Anciano , Gelatinasas/metabolismo , Serina Endopeptidasas/metabolismo , Serina Endopeptidasas/genética , Actinas/metabolismo , Fibroblastos Asociados al Cáncer/metabolismo , Fibroblastos Asociados al Cáncer/patología , Biomarcadores de Tumor/metabolismo , Alveolos Pulmonares/patología , Alveolos Pulmonares/metabolismo , Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Estadificación de Neoplasias , Adenocarcinoma in Situ/patología , Adenocarcinoma in Situ/metabolismo , AdultoRESUMEN
Background: Effective discrimination of lung adenocarcinoma (LUAD) in situ (AIS) from benign pulmonary nodules (BPN) is critical for the early diagnosis of AIS. Our pilot study in a small cohort of 90 serum samples has shown that serum interleukin 6 (IL-6) detection can distinguish AIS from BPN and health controls (HC). In this study, we intend to comprehensively define the diagnostic value of individual and combined detection of serum IL-6 related to the traditional tumor markers carcinoembryonic antigen (CEA) and cytokeratin 19 fragment (CYFRA21-1) for AIS. Methods: The diagnostic performance of serum IL-6 along with CEA and CYFRA21-1 were evaluated in a large cohort of 300 serum samples by a chemiluminescence immunoassay and an electrochemiluminescence immunoassay. A training set comprised of 65 AIS, 65 BPN, and 65 HC samples was used to develop the predictive model for AIS. Data obtained from an independent validation set was applied to evaluate and validate the predictive model. Results: In the training set, the levels of serum IL-6 and CEA in the AIS group were significantly higher than those in the BPN/HC group (P < 0.05). There was no significant difference in serum CYFRA21-1 levels between the AIS group and the BPN/HC group (P> 0.05). Serum IL-6 and CEA levels for AIS patients showed an area under the curve (AUC) of 0.622 with 23.1% sensitivity at 90.7% specificity, and an AUC of 0.672 with 24.6% sensitivity at 97.6% specificity, respectively. The combination of serum IL-6 and CEA presented an AUC of 0.739, with 60.0% sensitivity at 95.4% specificity. The combination of serum IL-6 and CEA showed an AUC of 0.767 for AIS patients, with 57.1% sensitivity at 91.4% specificity in the validation set. Conclusions: IL-6 shows potential as a prospective serum biomarker for the diagnosis of AIS, and the combination of serum IL-6 with CEA may contribute to increased accuracy in AIS diagnosis. However, it is worth noting that further research is still necessary to validate and optimize the diagnostic efficacy of these biomarkers and to address potential sensitivity limitations.
Asunto(s)
Adenocarcinoma in Situ , Adenocarcinoma del Pulmón , Antígenos de Neoplasias , Neoplasias Pulmonares , Nódulos Pulmonares Múltiples , Humanos , Adenocarcinoma in Situ/diagnóstico , Adenocarcinoma del Pulmón/diagnóstico , Antígeno Carcinoembrionario/sangre , Antígeno Carcinoembrionario/química , Interleucina-6/sangre , Interleucina-6/química , Queratina-19 , Pulmón/patología , Neoplasias Pulmonares/diagnóstico , Proyectos Piloto , Estudios ProspectivosRESUMEN
BACKGROUND: The pathological types of lung ground glass nodules (GGNs) show great significance to the clinical treatment. This study was aimed to predict pathological types of GGNs based on computed tomography (CT) quantitative parameters. METHODS: 389 GGNs confirmed by postoperative pathology were selected, including 138 cases of precursor glandular lesions [atypical adenomatous hyperplasia (AAH) and adenocarcinoma in situ (AIS)], 109 cases of microinvasive adenocarcinoma (MIA) and 142 cases of invasive adenocarcinoma (IAC). The morphological characteristics of nodules were evaluated subjectively by radiologist, as well as artificial intelligence (AI). RESULTS: In the subjective CT signs, the maximum diameter of nodule and the frequency of spiculation, lobulation and pleural traction increased from AAH+AIS, MIA to IAC. In the AI quantitative parameters, parameters related to size and CT value, proportion of solid component, energy and entropy increased from AAH+AIS, MIA to IAC. There was no significant difference between AI quantitative parameters and the subjective CT signs for distinguishing the pathological types of GGNs. CONCLUSIONS: AI quantitative parameters were valuable in distinguishing the pathological types of GGNs.
Asunto(s)
Adenocarcinoma in Situ , Adenocarcinoma , Neoplasias Pulmonares , Lesiones Precancerosas , Humanos , Neoplasias Pulmonares/patología , Inteligencia Artificial , Estudios Retrospectivos , Invasividad Neoplásica , Adenocarcinoma/patología , Adenocarcinoma in Situ/patología , Tomografía Computarizada por Rayos X/métodos , Lesiones Precancerosas/patología , Hiperplasia , Pulmón/diagnóstico por imagen , Pulmón/patologíaRESUMEN
Pulmonary adenocarcinoma (ADC) is a very diverse disease, both genetically and histologically, which displays extensive intratumor heterogeneity with numerous acquired mutations. ADC is the most common type of lung cancer and is believed to arise from adenocarcinoma in situ (AIS) which then progresses to minimally invasive adenocarcinoma (MIA). In patients of European ethnicity, we analyzed genetic mutations in AIS (n = 10) and MIA (n = 18) and compared the number of genetic mutations with advanced ADC (n = 2419). Using next-generation sequencing, the number of different mutations detected in both AIS (87.5%) and MIA (94.5%) were higher (p < 0.001) than in advanced ADC (53.7%). In contrast to the high number of mutations in Kirsten rat sarcoma virus gene (KRAS) in advanced ADC (34.6%), there was only one case of AIS with KRAS G12C mutation (3.5%; p < 0.001) and no cases of MIA with KRAS mutation (p < 0.001). In contrast to the modest prevalence of epidermal growth factor receptor (EGFR) mutations in advanced ADC (15.0%), the fraction of EGFR mutant cases was higher in both in AIS (22.2%) and MIA (59.5%; p < 0.001). The EGFR exon 19 deletion mutation was more common in both MIA (50%; n = 6/12) and ADC (41%; n = 149/363), whereas p.L858R was more prevalent in AIS (75%; n = 3/4). In contrast to pulmonary advanced ADC, KRAS driver mutations are less common, whereas mutations in EGFR are more common, in detectable AIS and MIA.
Asunto(s)
Adenocarcinoma in Situ , Adenocarcinoma del Pulmón , Adenocarcinoma , Neoplasias Pulmonares , Humanos , Proteínas Proto-Oncogénicas p21(ras)/genética , Adenocarcinoma in Situ/genética , Adenocarcinoma in Situ/patología , Adenocarcinoma del Pulmón/genética , Adenocarcinoma/patología , Neoplasias Pulmonares/metabolismo , Mutación , Receptores ErbB/metabolismoRESUMEN
Exosomes, extracellular vesicles released by cells, hold potential as diagnostic markers for the early detection of lung cancer. Despite their clinical promise, current technologies lack rapid and effective means to discriminate between exosomes derived from adenocarcinoma in situ (AIS) and early-stage invasive adenocarcinoma (IAC). This challenge arises from the intrinsic structural heterogeneity of exosomes, necessitating the development of advanced methodologies for precise differentiation. Here, we demonstrate a novel approach for plasma exosome detection utilizing multi-receptor surface-enhanced Raman spectroscopy (SERS) technology to differentiate between AIS and early-stage IAC. To accomplish this, we synthesized a stable and uniform two-dimensional SERS substrate (BC/Au NPs film) by fabricating gold nanoparticles onto bacterial cellulose. We then enhanced its capabilities by introducing multi-receptor SERS functionality via modifying the substrate with both low-specificity and physicochemical-selective molecules. Furthermore, by strategically combining all capturer-exosome SERS spectra, comprehensive "combined-SERS spectra" are reconstructed to enhance spectral variations of the exosome. Combining these features with partial least squares regression-discriminant analysis (PLS-DA) modeling significantly improved discriminatory accuracy, achieving 90% sensitivity and 95% specificity in distinguishing AIS from early-stage IAC. Our developed SERS sensor provides an effective method for early detection of lung cancer, thereby paving a new way for innovative advancements in diagnosing lung cancer.
Asunto(s)
Adenocarcinoma in Situ , Adenocarcinoma , Exosomas , Neoplasias Pulmonares , Nanopartículas del Metal , Humanos , Exosomas/química , Oro/química , Nanopartículas del Metal/química , Espectrometría Raman/métodos , Neoplasias Pulmonares/diagnósticoRESUMEN
OBJECTIVES: The longer-term impact of introducing human papillomavirus (HPV) testing into routine cervical cancer screening on precancer and cancer rates by histologic type has not been well described. Calendar trends in diagnoses were examined using data from Kaiser Permanente Northern California, which introduced triennial HPV and cytology co-testing in 2003 for women aged ≥30 years. METHODS: We examined trends in cervical precancer (cervical intraepithelial neoplasia grade 3 [CIN3] and adenocarcinoma in situ [AIS]) and cancer (squamous cell carcinoma [SCC] and adenocarcinoma [ADC]) diagnoses per 1000 screened during 2003-2018. We examined ratios of squamous vs. glandular diagnoses (SCC:ADC and CIN3:AIS). RESULTS: CIN3 and AIS diagnoses increased approximately 2% and 3% annually, respectively (ptrend < 0.001 for both). While SCC diagnoses decreased by 5% per annually (ptrend < 0.001), ADC diagnoses did not change. These patterns were generally observed within each age group (30-39, 40-49, and 50-64 years). ADC diagnoses per 1000 screened did not change even among those who underwent co-testing starting in 2003-2006. SCC:ADC decreased from approximately 2.5:1 in 2003-2006 to 1.3:1 in 2015-2018 while the CIN3:AIS remained relatively constant, â¼10:1. CONCLUSIONS: Since its introduction at KPNC, co-testing increased the detection of CIN3 over time, which likely caused a subsequent reduction of SCC. However, there has been no observed decrease in ADC. One possible explanation for lack of effectiveness against ADC is the underdiagnosis of AIS. Novel strategies to identify and treat women at high risk of ADC need to be developed and clinically validated.
Asunto(s)
Detección Precoz del Cáncer , Infecciones por Papillomavirus , Displasia del Cuello del Útero , Neoplasias del Cuello Uterino , Humanos , Femenino , Neoplasias del Cuello Uterino/diagnóstico , Neoplasias del Cuello Uterino/virología , Neoplasias del Cuello Uterino/epidemiología , Neoplasias del Cuello Uterino/patología , California/epidemiología , Adulto , Persona de Mediana Edad , Displasia del Cuello del Útero/diagnóstico , Displasia del Cuello del Útero/epidemiología , Displasia del Cuello del Útero/virología , Displasia del Cuello del Útero/patología , Detección Precoz del Cáncer/métodos , Detección Precoz del Cáncer/estadística & datos numéricos , Detección Precoz del Cáncer/tendencias , Infecciones por Papillomavirus/diagnóstico , Infecciones por Papillomavirus/epidemiología , Infecciones por Papillomavirus/patología , Infecciones por Papillomavirus/virología , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/epidemiología , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/virología , Adenocarcinoma in Situ/patología , Adenocarcinoma in Situ/diagnóstico , Adenocarcinoma in Situ/epidemiología , Adenocarcinoma in Situ/virología , Lesiones Precancerosas/diagnóstico , Lesiones Precancerosas/epidemiología , Lesiones Precancerosas/virología , Lesiones Precancerosas/patología , Anciano , Frotis Vaginal/tendencias , Frotis Vaginal/métodos , Adenocarcinoma/diagnóstico , Adenocarcinoma/epidemiología , Adenocarcinoma/patología , Adenocarcinoma/virología , Virus del Papiloma Humano , CitologíaRESUMEN
BACKGROUND: Cytology and high-risk human papilloma virus (hrHPV) cotesting is the mainstay in the detection of cervical carcinoma. METHODS: Endocervical adenocarcinoma (EAC) is divided into HPV-associated adenocarcinoma (HPVA) and HPV-independent adenocarcinoma (HPVI) by the World Health Organization classification (2020). The detection effect of cotesting is suggested to be different among EAC subtypes and precursors, but has not well-documented yet. In this study, the authors retrospectively analyzed cotesting among adenocarcinoma in situ (AIS), HPVA, and HPVI. The cohort included 569 AIS and 498 EAC consisting of 371 (74.5%) HPVA, 111 (22.3%) HPVI, and 16 (3.2%) adenocarcinoma, not otherwise specified. RESULTS: The authors found that AIS patients were significantly younger than HPVA and HPVI (mean ± SD, years: 40.7 ± 8.6; HPVA, 44.8 ± 9.3; HPVI, 50.0 ± 11.3; p < .001) and had a higher prevalence of concurrent squamous intraepithelial lesions (75.5%, HPVA, 37.2%; HPVI, 12.6%; p < .001). The detection rate of hrHPV test or cytology was substantially higher in AIS and HPVA than in HPVI (97.7% and 90.2% vs. 16.5%, p < .001, or 71.1% and 71.9% vs. 60.7%, p = .042, respectively). Cytology and hrHPV cotesting was superior to a single test in the detection of EAC and AIS. The detection rate of cotesting amounted to 100% in AIS and 94.3% in HPVA but was substantially lower in HPVI (72.2%) (p < .001). CONCLUSIONS: The authors conclude that cytology and hrHPV cotesting can maximize the detection effect for HPVA and AIS but is not optimal for HPVI.
Asunto(s)
Adenocarcinoma , Infecciones por Papillomavirus , Neoplasias del Cuello Uterino , Humanos , Femenino , Estudios Retrospectivos , Neoplasias del Cuello Uterino/virología , Neoplasias del Cuello Uterino/diagnóstico , Neoplasias del Cuello Uterino/patología , Infecciones por Papillomavirus/virología , Infecciones por Papillomavirus/diagnóstico , Infecciones por Papillomavirus/patología , Infecciones por Papillomavirus/complicaciones , Adulto , Adenocarcinoma/virología , Adenocarcinoma/patología , Adenocarcinoma/diagnóstico , Persona de Mediana Edad , Papillomaviridae/aislamiento & purificación , Frotis Vaginal/métodos , Displasia del Cuello del Útero/virología , Displasia del Cuello del Útero/diagnóstico , Displasia del Cuello del Útero/patología , Displasia del Cuello del Útero/epidemiología , Citodiagnóstico/métodos , Lesiones Precancerosas/virología , Lesiones Precancerosas/diagnóstico , Lesiones Precancerosas/patología , Adenocarcinoma in Situ/virología , Adenocarcinoma in Situ/patología , Adenocarcinoma in Situ/diagnóstico , CitologíaRESUMEN
Serous tubal intraepithelial carcinoma (STIC) is the fallopian tube precursor lesion for most cases of pelvic high-grade serous carcinoma (HGSC). To date, the morphologic, molecular, and clinical heterogeneity of STIC and a less atypical putative precursor lesion, termed serous tubal intraepithelial lesion, has not been well characterized. Better understanding of precursor heterogeneity could impact the clinical management of women with incidental STICs (without concurrent carcinoma) identified in cases of prophylactic or opportunistic salpingectomy. This study analyzed morphologic and molecular features of 171 STICs and 21 serous tubal intraepithelial lesions. We assessed their histologic features, Ki-67 and p53 staining patterns, and genome-wide DNA copy number alterations. We classified all precursor lesions into 2 morphologic subtypes, one with a flat surface (Flat) and the other characterized by budding, loosely adherent, or detached (BLAD) morphology. On the basis of pathology review by a panel of 8 gynecologic pathologists, we found 87 BLAD, 96 Flat, and 9 indeterminate lesions. As compared with Flat lesions, BLAD lesions were more frequently diagnostic of STIC ( P <0.0001) and were found concurrently with HGSC ( P <0.0001). BLAD morphology was also characterized by higher Ki-67 proliferation index ( P <0.0001), presence of epithelial stratification ( P <0.0001), and increased lymphocyte density ( P <0.0001). BLAD lesions also exhibited more frequent DNA copy number gain/amplification at the CCNE1 or CMYC loci canonical to HGSCs ( P <0.0001). Both BLAD morphology and STIC diagnoses are independent risk factors for an elevated Ki-67 proliferation index. No correlation was observed between BLAD and Flat lesions with respect to patient age, presence of germline BRCA1/2 mutation, or p53 staining pattern. These findings suggest that tubal precursor lesions are morphologically and molecularly heterogeneous, laying the foundation for further studies on the pathogenesis of HGSC initiation and identifying histologic features predictive of poor patient outcomes.
Asunto(s)
Adenocarcinoma in Situ , Carcinoma in Situ , Carcinoma , Cistadenocarcinoma Seroso , Neoplasias de las Trompas Uterinas , Neoplasias Ováricas , Femenino , Humanos , Proteína BRCA1 , Carcinoma in Situ/genética , Carcinoma in Situ/patología , Neoplasias Ováricas/patología , Antígeno Ki-67 , Proteína p53 Supresora de Tumor/genética , Proteína BRCA2 , Neoplasias de las Trompas Uterinas/genética , Neoplasias de las Trompas Uterinas/patología , Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/patología , ADNRESUMEN
BACKGROUND: Cervical cancer is the fourth most common cancer among women globally and has a strong association with Human Papillomavirus (HPV) infection. Stratified mucinproducing intraepithelial lesion (SMILE), a variant of Adenocarcinoma in situ (AIS), is a rare cervical precancer lesion that is often missed or detected incidentally. CASE PRESENTATION: The present case report briefs the finding of a 39-year-old woman who presented to the gynecological outpatient department with complaints of vaginal discharge for 6-8 months. She had no history of irregular menstrual cycles or postcoital bleeding. Her routine Pap smear revealed atypical squamous cells of undetermined significance (ASCUS) and was positive for HPV-16 type. Her cervical biopsy report revealed AIS and her histopathological report of hysterectomy revealed SMILE, a variant of AIS. DISCUSSION: The SMILE variant of AIS is a rare cervical precancerous lesion characterized by the morphological overlap of both squamous intraepithelial lesions and AIS. It is often difficult to diagnose on Pap smear and is commonly associated with high-risk HPV infections. The management of SMILE is the same as that for AIS, which is the excisional procedure followed by a hysterectomy if the margins are negative and depending on the fertility desires of the patient, followed by regular follow-up with HPV testing. CONCLUSION: SMILE is a rare variant of AIS, which is often missed on cytological screening of the cervix. It is commonly associated with high-risk types of HPV. Hence, incorporating HPV testing in the screening of cervical cancer is important and recommended to increase the overall sensitivity of screening for adenocarcinoma lesions.
Asunto(s)
Papillomavirus Humano 16 , Histerectomía , Prueba de Papanicolaou , Infecciones por Papillomavirus , Neoplasias del Cuello Uterino , Humanos , Femenino , Adulto , Neoplasias del Cuello Uterino/virología , Neoplasias del Cuello Uterino/patología , Neoplasias del Cuello Uterino/cirugía , Infecciones por Papillomavirus/virología , Infecciones por Papillomavirus/diagnóstico , Infecciones por Papillomavirus/patología , Infecciones por Papillomavirus/complicaciones , Papillomavirus Humano 16/aislamiento & purificación , Mucinas/metabolismo , Adenocarcinoma in Situ/virología , Adenocarcinoma in Situ/patología , Adenocarcinoma in Situ/cirugía , Displasia del Cuello del Útero/virología , Displasia del Cuello del Útero/patología , Displasia del Cuello del Útero/cirugía , Frotis Vaginal , Cuello del Útero/patología , Cuello del Útero/virología , Cuello del Útero/cirugía , BiopsiaRESUMEN
OBJECTIVES: Evaluation of the results of treatment of adenocarcinoma in situ by loop electrosurgical excision procedure and the safety of a conservative strategy. METHODS: Identification of all cases of adenocarcinoma in situ treated by loop electrosurgical excision procedure at our institution and follow-up by a conservative strategy. Completeness of the identification of all cases was secured by data from the National Pathology Registry. The treatment strategy was based on cytologic follow-up performed by a general practitioner and, irrespective of margin status of the cone, only the results of the postoperative surveillance were indicative of further treatment. RESULTS: A total of 224 patients were identified. The overall recurrence rate with a mean follow-up time of 87.8 months was 7.6% (17/224). The recurrence rate in patients with involved margins was significantly higher than in patients with uninvolved margins, 15.7% vs 5.2%, respectively. Six recurrences were diagnosed at first examination 6 months postconization in patients with involved margins. They were treated with hysterectomy in 4 cases and reconization in 1 case. If involvement of margins alone had been an indication of further therapy (hysterectomy or reconization) immediately after conization, the conservative management strategy prevented 46 surgical procedures. Two cases of invasive cancer were diagnosed during follow-up, 150 months and 196 months after primary treatment, and after normal follow-up examinations. These 2 cases must be considered de novo cases and cannot be considered treatment failures. CONCLUSION: The conservative management strategy thus seems safe, and unnecessary surgical procedures were avoided.
Asunto(s)
Adenocarcinoma in Situ , Displasia del Cuello del Útero , Neoplasias del Cuello Uterino , Femenino , Humanos , Adenocarcinoma in Situ/cirugía , Adenocarcinoma in Situ/diagnóstico , Neoplasias del Cuello Uterino/diagnóstico , Electrocirugia/métodos , Resultado del Tratamiento , Estudios Retrospectivos , Conización/métodos , Displasia del Cuello del Útero/cirugíaRESUMEN
HPV-independent in situ adenocarcinomas have been only recently added to the WHO 2020 classification. To date, little information has been published about HPVindependent precursor lesions. In particular, regardiong the extremely rare cervical endometrioid type adenocarcinoma thought to arise in the setting of cervical endometriosis, a premalignant lesion is still not well defined. In this short communication we describe a possible precursor to invasive cervical endometrioid type adenocarcinoma in a 39-yr-old patient, with a previous history of breast cancer.
Asunto(s)
Adenocarcinoma in Situ , Carcinoma Endometrioide , Neoplasias del Cuello Uterino , Femenino , Humanos , Cuello del Útero/patología , Adenocarcinoma in Situ/patología , Carcinoma Endometrioide/patología , Neoplasias del Cuello Uterino/patologíaRESUMEN
OBJECTIVE: To determine the baseline and cumulative risk of cervical intraepithelial neoplasia (CIN)3 and invasive cervical cancer in participants referred to colposcopy with high-grade cytology and Asunto(s)
Adenocarcinoma in Situ
, Células Escamosas Atípicas del Cuello del Útero
, Carcinoma in Situ
, Carcinoma de Células Escamosas
, Infecciones por Papillomavirus
, Lesiones Intraepiteliales Escamosas
, Displasia del Cuello del Útero
, Neoplasias del Cuello Uterino
, Embarazo
, Humanos
, Femenino
, Neoplasias del Cuello Uterino/diagnóstico
, Neoplasias del Cuello Uterino/epidemiología
, Neoplasias del Cuello Uterino/patología
, Colposcopía
, Displasia del Cuello del Útero/patología
, Células Escamosas Atípicas del Cuello del Útero/patología
, Frotis Vaginal
, Infecciones por Papillomavirus/diagnóstico
, Papillomaviridae
RESUMEN
AIMS: The invasive pattern in HPV-associated endocervical adenocarcinoma (HPVA) has prognostic value. Non-destructive (pattern A) HPVA has excellent prognosis mirroring adenocarcinoma in-situ (AIS). However, the rare occurrence of ovarian spread in these tumours suggests aggressiveness in a subset of patients with these otherwise indolent lesions. We hypothesise that AIS/pattern A HPVA with ovarian metastases are biologically different than metastatic destructively invasive HPVA. METHODS AND RESULTS: Samples from patients with HPVA and synchronous or metachronous metastases were retrieved and reviewed to confirm diagnosis and determine the Silva pattern in the primary lesion. For each case, normal tissue, cervical tumour and at least one metastasis underwent comprehensive sequencing using a 447-gene panel. Pathogenic single-nucleotide variants and segmental copy-number alterations (CNA), tumour mutational burden and molecular signatures were evaluated and compared between primary and metastases and among invasive pattern categories. We identified 13 patients: four had AIS/pattern A primaries, while nine had pattern B/C tumours. All AIS/pattern A lesions had metastasis only to ovary; 50% of patients with ovarian involvement, regardless of invasive pattern, also had involvement of the endometrium and/or fallopian tube mucosa by HPVA. In the ovary, AIS/pattern A HPVA showed deceptive well-differentiated glands, often with adenofibroma-like appearance. Conversely, pattern C HPVAs consistently showed overt infiltrative features in the ovary. Sequencing confirmed the genetic relationship between primary and metastatic tumours in each case. PIK3CA alterations were identified in three of four AIS/pattern A HPVAs and three of eight pattern B/C tumours with sequenced metastases. Pattern C tumours showed a notably higher number of CNA in primary tumours compared to pattern A/B tumours. Only one metastatic AIS/pattern A HPVA had a novel pathogenic variant compared to the primary. Conversely, five of eight pattern B/C tumours with sequenced metastases developed novel pathogenic variants in the metastasis not seen in the primary. All four AIS/pattern A patients were alive and free of disease at 31, 47, 58 and 212 months after initial diagnosis. Conversely, cancer-related death was documented in five of nine pattern B/C patients with follow-up at 7, 20, 20, 43 and 87 months. CONCLUSION: Morphologically and genomically, AIS/pattern A HPVA with secondary ovarian involvement appears distinct from destructively invasive tumours. In at least a subset of these cases, ovarian spread appears to occur via trans-Mullerian superficial extension, different from the stromal and lymphatic vascular spread typical of more aggressive tumours (pattern C). These differences may explain the indolent outcome observed in the rare subset of patients with AIS/pattern A HPVA and ovarian metastasis. Our data underscore the potential for conservative surgical management approaches to pattern A HPVA.
Asunto(s)
Adenocarcinoma in Situ , Adenocarcinoma , Neoplasias Ováricas , Infecciones por Papillomavirus , Neoplasias del Cuello Uterino , Femenino , Humanos , Neoplasias del Cuello Uterino/genética , Neoplasias del Cuello Uterino/diagnóstico , Infecciones por Papillomavirus/complicaciones , Adenocarcinoma/patología , Neoplasias Ováricas/genética , Neoplasias Ováricas/secundarioRESUMEN
OBJECTIVES/PURPOSE: The reproducibility and sensitivity of image-based colposcopy is low, but agreement on lesion presence and location remains to be explored. Here, we investigate the interobserver agreement on lesions on colposcopic images by evaluating and comparing marked lesions on digitized colposcopic images between colposcopists. METHODS: Five colposcopists reviewed images from 268 colposcopic examinations. Cases were selected based on histologic diagnosis, i.e., normal/cervical intraepithelial neoplasia (CIN)1 ( n = 50), CIN2 ( n = 50), CIN3 ( n = 100), adenocarcinoma in situ ( n = 53), and cancer ( n = 15). We obtained digitized time-series images every 7-10 seconds from before acetic acid application to 2 minutes after application. Colposcopists were instructed to digitally annotate all areas with acetowhitening or suspect of lesions. To estimate the agreement on lesion presence and location, we assessed the proportion of images with annotations and the proportion of images with overlapping annotated area by at least 4 (4+) colposcopists, respectively. RESULTS: We included images from 241 examinations (1 image from each) with adequate annotations. The proportion with a least 1 lesion annotated by 4+ colposcopists increased by severity of histologic diagnosis. Among the CIN3 cases, 84% had at least 1 lesion annotated by 4+ colposcopists, whereas 54% of normal/CIN1 cases had a lesion annotated. Notably, the proportion was 70% for adenocarcinoma in situ and 71% for cancer. Regarding lesion location, there was no linear association with severity of histologic diagnosis. CONCLUSION: Despite that 80% of the CIN2 and CIN3 cases were annotated by 4+ colposcopists, we did not find increasing agreement on lesion location with histology severity. This underlines the subjective nature of colposcopy.
Asunto(s)
Adenocarcinoma in Situ , Displasia del Cuello del Útero , Neoplasias del Cuello Uterino , Femenino , Embarazo , Humanos , Colposcopía/métodos , Neoplasias del Cuello Uterino/diagnóstico , Neoplasias del Cuello Uterino/patología , Reproducibilidad de los Resultados , Displasia del Cuello del Útero/patologíaRESUMEN
BACKGROUND: In Taiwan, lung cancers occur predominantly in never-smokers, of whom nearly 60% have stage IV disease at diagnosis. We aimed to assess the efficacy of low-dose CT (LDCT) screening among never-smokers, who had other risk factors for lung cancer. METHODS: The Taiwan Lung Cancer Screening in Never-Smoker Trial (TALENT) was a nationwide, multicentre, prospective cohort study done at 17 tertiary medical centres in Taiwan. Eligible individuals had negative chest radiography, were aged 55-75 years, had never smoked or had smoked fewer than 10 pack-years and stopped smoking for more than 15 years (self-report), and had one of the following risk factors: a family history of lung cancer; passive smoke exposure; a history of pulmonary tuberculosis or chronic obstructive pulmonary disorders; a cooking index of 110 or higher; or cooking without using ventilation. Eligible participants underwent LDCT at baseline, then annually for 2 years, and then every 2 years up to 6 years thereafter, with follow-up assessments at each LDCT scan (ie, total follow-up of 8 years). A positive scan was defined as a solid or part-solid nodule larger than 6 mm in mean diameter or a pure ground-glass nodule larger than 5 mm in mean diameter. Lung cancer was diagnosed through invasive procedures, such as image-guided aspiration or biopsy or surgery. Here, we report the results of 1-year follow-up after LDCT screening at baseline. The primary outcome was lung cancer detection rate. The p value for detection rates was estimated by the χ2 test. Univariate and multivariable logistic regression analyses were used to assess the association between lung cancer incidence and each risk factor. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of LDCT screening were also assessed. This study is registered with ClinicalTrials.gov, NCT02611570, and is ongoing. FINDINGS: Between Dec 1, 2015, and July 31, 2019, 12â011 participants (8868 females) were enrolled, of whom 6009 had a family history of lung cancer. Among 12â011 LDCT scans done at baseline, 2094 (17·4%) were positive. Lung cancer was diagnosed in 318 (2·6%) of 12â011 participants (257 [2·1%] participants had invasive lung cancer and 61 [0·5%] had adenocarcinomas in situ). 317 of 318 participants had adenocarcinoma and 246 (77·4%) of 318 had stage I disease. The prevalence of invasive lung cancer was higher among participants with a family history of lung cancer (161 [2·7%] of 6009 participants) than in those without (96 [1·6%] of 6002 participants). In participants with a family history of lung cancer, the detection rate of invasive lung cancer increased significantly with age, whereas the detection rate of adenocarcinoma in situ remained stable. In multivariable analysis, female sex, a family history of lung cancer, and age older than 60 years were associated with an increased risk of lung cancer and invasive lung cancer; passive smoke exposure, cumulative exposure to cooking, cooking without ventilation, and a previous history of chronic lung diseases were not associated with lung cancer, even after stratification by family history of lung cancer. In participants with a family history of lung cancer, the higher the number of first-degree relatives affected, the higher the risk of lung cancer; participants whose mother or sibling had lung cancer were also at an increased risk. A positive LDCT scan had 92·1% sensitivity, 84·6% specificity, a PPV of 14·0%, and a NPV of 99·7% for lung cancer diagnosis. INTERPRETATION: TALENT had a high invasive lung cancer detection rate at 1 year after baseline LDCT scan. Overdiagnosis could have occurred, especially in participants diagnosed with adenocarcinoma in situ. In individuals who do not smoke, our findings suggest that a family history of lung cancer among first-degree relatives significantly increases the risk of lung cancer as well as the rate of invasive lung cancer with increasing age. Further research on risk factors for lung cancer in this population is needed, particularly for those without a family history of lung cancer. FUNDING: Ministry of Health and Welfare of Taiwan.