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OBJECTIVE: Intraductal Papillary Mucinous Neoplasms (IPMNs) are cystic lesions and bona fide precursors for pancreatic ductal adenocarcinoma (PDAC). Recently, we showed that acinar to ductal metaplasia, an injury repair program, is characterized by a transcriptomic program similar to gastric spasmolytic polypeptide expressing metaplasia (SPEM), suggesting common mechanisms of reprogramming between the stomach and pancreas. The aims of this study were to assay IPMN for pyloric markers and to identify molecular drivers of this program. DESIGN: We analyzed RNA-seq studies of IPMN for pyloric markers, which were validated by immunostaining in patient samples. Cell lines expressing Kras G12D +/- GNAS R201C were manipulated to identify distinct and overlapping transcriptomic programs driven by each oncogene. A PyScenic-based regulon analysis was performed to identify molecular drivers in the pancreas. Expression of candidate drivers was evaluated by RNA-seq and immunostaining. RESULTS: Pyloric markers were identified in human IPMN. GNAS R201C drove expression of these markers in cell lines and siRNA targeting of GNAS R201C or Kras G12D demonstrates that GNAS R201C amplifies a mucinous, pyloric phenotype. Regulon analysis identified a role for transcription factors SPDEF, CREB3L1, and CREB3L4, which are expressed in patient samples. siRNA-targeting of Spdef inhibited mucin production. CONCLUSION: De novo expression of a SPEM phenotype has been identified in pancreatitis and a pyloric phenotype in Kras G12D -driven PanIN and Kras G12D ;GNAS R201C -driven IPMN, suggesting common mechanisms of reprogramming between these lesions and the stomach. A transition from a SPEM to pyloric phenotype may reflect disease progression and/or oncogenic mutation. IPMN-specific GNAS R201C amplifies a mucinous phenotype, in part, through SPDEF.
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Hepatocyte Nuclear Factor 4-alpha (HNF4α) comprises a nuclear receptor superfamily of ligand-dependent transcription factors that yields twelve isoforms in humans, classified into promoters P1 or P2-associated groups with specific functions. Alterations in HNF4α isoforms have been associated with tumorigenesis. However, the distribution of its isoforms during progression from dysplasia to malignancy has not been studied, nor has it yet been studied in intraductal papillary mucinous neoplasms, where both malignant and pre-malignant forms are routinely clinically identified. We examined the expression patterns of pan-promoter, P1-specific, and P2-specific isoform groups in normal pancreatic components and IPMNs. Pan-promoter, P1 and P2 nuclear expression were weakly positive in normal pancreatic components. Nuclear expression for all isoform groups was increased in low-grade IPMN, high-grade IPMN, and well-differentiated invasive adenocarcinoma. Poorly differentiated invasive components in IPMNs showed loss of all forms of HNF4α. Pan-promoter, and P1-specific HNF4α expression showed shifts in subnuclear and sub-anatomical distribution in IPMN, whereas P2 expression was consistently nuclear. Tumor cells with high-grade dysplasia at the basal interface with the stroma showed reduced expression of P1, while P2 was equally expressed in both components. Additional functional studies are warranted to further explore the mechanisms underlying the spatial and differential distribution of HNF4α isoforms in IPMNs.
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Adenocarcinoma , Carcinoma Ductal Pancreático , Neoplasias Intraductais Pancreáticas , Neoplasias Pancreáticas , Humanos , Neoplasias Intraductais Pancreáticas/patologia , Neoplasias Pancreáticas/patologia , Pâncreas/metabolismo , Adenocarcinoma/patologia , Hiperplasia/patologia , Isoformas de Proteínas/metabolismo , Carcinoma Ductal Pancreático/patologiaRESUMO
Distinguishing lupus erythematosus panniculitis (LEP) from subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is a diagnostic challenge with important clinical implications. Immunohistochemical expression of interferon regulatory factor 8 (IRF8) has been shown to highlight cells with plasmacytoid dendritic cell differentiation. Considering that the presence of plasmacytoid dendritic cells highlighted by CD123 immunolabeling is a well-described feature that supports LEP over SPTCL, we hypothesized that IRF8 immunohistochemistry can be used as a diagnostic test to improve accuracy in differentiating LEP from SPTCL. In this study, we assessed the expression of IRF8, CD123, and CD20 in 35 cutaneous biopsies from 31 distinct patients, which included 22 cases of LEP and 13 cases of SPTCL. We found that clusters of IRF8-positive cells within the dermis, and away from subcutaneous fat, could discriminate LEP from SPTCL ( P =0.005). Similarly, CD123-positive clusters in any location were observed in LEP but absent in all cases of SPTCL. In addition, we found that dermal CD20-predominant lymphoid aggregates could help discriminate LEP from SPTCL ( P =0.022). As individual assays, IRF8, CD123, and CD20 were highly specific (100%, 100%, and 92%, respectively) though poorly sensitive (45%, 29%, and 50%, respectively). However, a panel combining IRF8, CD123, and CD20, with at least 1 positive marker was more accurate than any individual marker by receiver operating characteristic curve analysis. Our study provides a rationale for potentially including IRF8 as part of an immunohistochemical panel composed of other currently available markers used to differentiate LEP from SPTCL.
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Paniculite de Lúpus Eritematoso , Paniculite , Humanos , Paniculite de Lúpus Eritematoso/diagnóstico , Paniculite de Lúpus Eritematoso/metabolismo , Paniculite de Lúpus Eritematoso/patologia , Subunidade alfa de Receptor de Interleucina-3 , Paniculite/diagnóstico , Paniculite/patologia , Fatores Reguladores de InterferonRESUMO
BACKGROUND: Lymphadenomas are rare benign tumors of the major salivary glands that are further classified as sebaceous and non-sebaceous. No association with viruses has been reported so far. Little is known about the mechanisms that allow lymphadenomas to undergo malignant transformation. Among these rare instances, there has never been a malignant transformation to Epstein-Barr virus (EBV)-associated lymphoepithelial carcinoma. METHODS: Clinical data of the reported case were retrieved from the patient's electronic medical record. Hematoxylin & eosin-stained slides, immunohistochemical tests, and in situ hybridization performed for routine diagnostic purposes were reviewed. RESULTS: We report a salivary gland sebaceous lymphadenoma in which the luminal components were mostly replaced by malignant epithelial cells with markedly atypical nuclear features. Presence of EBV was demonstrated in all components by EBER. The morphological and immunohistochemical findings were consistent with a lymphoepithelial carcinoma arising from a sebaceous lymphadenoma. CONCLUSION: We report the first case of an Epstein-Barr virus-associated lymphoepithelial carcinoma arising from a sebaceous lymphadenoma.
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Carcinoma de Células Escamosas , Infecções por Vírus Epstein-Barr , Neoplasias Parotídeas , Neoplasias das Glândulas Salivares , Humanos , Herpesvirus Humano 4/genética , Infecções por Vírus Epstein-Barr/complicações , Carcinoma de Células Escamosas/patologia , Neoplasias das Glândulas Salivares/patologia , Hibridização In Situ , Neoplasias Parotídeas/patologiaRESUMO
Human papillomavirus-associated vulvar intraepithelial neoplasia (high-grade squamous intraepithelial neoplasia [HSIL] or VIN of usual type) is a lesion characterized by atypia extending from the basal layer to the upper epidermis. There are only rare reports of vulvar intraepithelial morphology exhibiting a pagetoid pattern of intraepithelial dissemination. We herein report two cases of vulvar HSIL in which a pagetoid pattern of spread and a largely uninvolved basal layer represented a diagnostic pitfall for extramammary Paget disease. Nuclear atypia reminiscent of HSIL in addition to expression of p16, KRT5/6, and p40 were however in favor of pagetoid HSIL. Although there is morphological and immunohistochemical overlap between these two entities, an accurate diagnosis is important, since an erroneous diagnosis of vulvar extramammary Paget disease may lead to an extensive workup comprising radiological imaging, colonoscopy, and cystoscopy.
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Carcinoma in Situ , Carcinoma de Células Escamosas , Doença de Paget Extramamária , Neoplasias Vulvares , Feminino , Humanos , Doença de Paget Extramamária/diagnóstico , Doença de Paget Extramamária/cirurgia , Vulva/patologia , Neoplasias Vulvares/patologia , Carcinoma in Situ/diagnóstico , Carcinoma in Situ/patologia , Carcinoma de Células Escamosas/patologia , Epiderme/patologiaRESUMO
Uterine leiomyoma with massive lymphoid infiltration is characterized by a dense lymphoid infiltrate and germinal centers sparing the adjacent myometrium. Only few reports describe this entity and its etiology is unknown. This rare lesion may also exhibit lymphocytic vasculopathy but this has only been reported in the setting of GnRH agonist exposure. We report 2 cases of uterine leiomyoma with massive lymphoid infiltration in which only 1 patient was exposed to GnRH agonists. In both cases, histopathologic analysis showed thick-walled vessels with swollen endothelial cells showing evidence of intramural lymphocytic infiltration, red blood cell extravasation, and medial edema. This constellation of findings represented frank vascular damage and lymphocytic vasculopathy. Our findings suggest that lymphocytic vasculopathy in these lesions may be secondary to factors other than GnRH agonists. Furthermore, both cases showed an angiocentric disposition of germinal centers that has scarcely been alluded to in prior reports. This finding may provide a clue in accurately recognizing leiomyoma with massive lymphoid infiltration. Recognition of this lesion will allow one to avoid mistaking it for mimickers such as inflammatory myofibroblastic tumor, lymphoid malignancies, or other inflammatory processes.
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Leiomioma , Neoplasias Uterinas , Feminino , Humanos , Neoplasias Uterinas/patologia , Células Endoteliais/patologia , Leiomioma/patologia , Centro Germinativo/patologia , Hormônio Liberador de GonadotropinaRESUMO
Vulvar squamous cell carcinoma of the vulva (VSCC) with sarcomatoid features is a rare variant characterized by spindle-cell morphology and occasional heterologous elements. They are difficult to evaluate due to rarity and lack unified nomenclature and histopathologic criteria. Eight cases of sarcomatoid VSCC were retrieved from archival electronic medical records from 2013 to 2021. Patients often presented at a mean age of 78-yr-old at stage FIGO (2018) III or above. The mean greatest diameter was 4.5 cm and mean depth of invasion was 11.5 mm. Spindle cells exhibited fascicular, nested, and cord-like growth patterns, though a haphazard arrangement or a mix of patterns was frequently observed. The sarcomatoid component frequently arose in the context of prior conventional VSCC treated with radiation therapy (n=6, 75% and chemotherapy (n=5, 63%) with latency periods of 5.2 and 5.4 yr, respectively. Associated lesions included differentiated vulvar intraepithelial neoplasia (n=4, 50%), lichen sclerosus (n=5, 63%), and vulvar acanthosis with altered differentiation (n=1, 13%). Immunohistochemistry showed that VSCC with sarcomatoid features aberrantly expressed p53 (n=4, 60%) through diffuse overexpression or null-type patterns. P16 was invariably negative in all cases. These findings suggest that VSCC with sarcomatoid features does not arise from the HPV-related carcinogenic pathway, and that a subset may also arise from the TP53-independent pathway. Recognizing sarcomatoid morphology in VSCC is important since it may confer an elevated risk of nodal metastasis and poorer survival. Larger studies are required to assess the etiology and prognostic implications of VSCC with sarcomatoid features.
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Carcinoma in Situ , Carcinoma de Células Escamosas , Infecções por Papillomavirus , Neoplasias Vulvares , Feminino , Humanos , Idoso , Infecções por Papillomavirus/patologia , Neoplasias Vulvares/patologia , Carcinoma in Situ/patologia , Vulva/patologia , Carcinoma de Células Escamosas/patologiaRESUMO
The development of neural structures within tumors is now considered vital for carcinogenesis. However, the time course of this development in human pre-invasive neoplasia has been incompletely described. Therefore, we performed a detailed analysis of nerves across the neoplastic spectrum in resected intraductal papillary mucinous neoplasms (IPMNs) of the pancreas. Histology and multiplexed immunochemistry demonstrated that nerve density increased from low-grade (LG) to high-grade dysplasia (HG) but did not further increase once invasive IPMN (INV IPMN) was present. Higher nerve density correlated with increasing expression of nerve growth factor (NGF) by the tumor cells. Intra-tumoral nerves were immature and lacked markers of sympathetic, parasympathetic, and sensory lineages. Here, we show for the first time the presence of neural precursor cells (NPCs) within the stroma of pancreatic tumors. The density of these doublecortin (DCX)-positive NPCs increased from LG to HG, but not from HG to INV IPMN. We conclude that peak neural density of tumors is reached in high-grade dysplasia (often termed carcinoma in situ) rather than after invasion. These findings suggest that nerve-tumor interactions are important in IPMN progression and may serve as the basis for future mechanistic studies and novel therapeutic modalities. © 2022 The Pathological Society of Great Britain and Ireland.
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Adenocarcinoma Mucinoso , Carcinoma Ductal Pancreático , Células-Tronco Neurais , Neoplasias Intraductais Pancreáticas , Neoplasias Pancreáticas , Adenocarcinoma Mucinoso/patologia , Carcinoma Ductal Pancreático/patologia , Humanos , Hiperplasia/patologia , Células-Tronco Neurais/metabolismo , Neurônios/patologia , Pâncreas/patologia , Neoplasias Intraductais Pancreáticas/patologia , Neoplasias Pancreáticas/patologiaRESUMO
We present the case of a 31-year-old woman who underwent surgical excision for a polypoid, vulvar lesion. Histopathological analysis showed a diffuse myxoid stroma admixed with scant collagen fibrils. Thin-walled and branching blood vessels were prominent, with a mild perivascular lymphocytic infiltrate. Cytologically bland spindle cells with inconspicuous nucleoli were immersed in a loose myxoid stroma. This combination of histopathological features along with multinodularity in the subcutaneous fat raised concern for deep angiomyxoma, a locally destructive neoplasm. Among our differential of myxoid lesions of the vulva, we ultimately favored the diagnosis of vulvar cutaneous myxoma. Upon further investigation, we learned that our patient was indeed known for the Carney complex. We highlight that vulvar cutaneous myxomas arising in the context of the Carney complex pose a significant diagnostic challenge for pathologists and should not be overdiagnosed as aggressive lesions such as deep angiomyxoma or other malignant stromal neoplasms.
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Complexo de Carney/patologia , Neoplasias Cutâneas/patologia , Neoplasias Vulvares/patologia , Adulto , Biomarcadores Tumorais/metabolismo , Complexo de Carney/diagnóstico , Complexo de Carney/metabolismo , Feminino , Humanos , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/metabolismo , Neoplasias Vulvares/diagnóstico , Neoplasias Vulvares/metabolismoRESUMO
SIGNIFICANCE: Prostate cancer is the most common cancer among men. An accurate diagnosis of its severity at detection plays a major role in improving their survival. Recently, machine learning models using biomarkers identified from Raman micro-spectroscopy discriminated intraductal carcinoma of the prostate (IDC-P) from cancer tissue with a ≥85 % detection accuracy and differentiated high-grade prostatic intraepithelial neoplasia (HGPIN) from IDC-P with a ≥97.8 % accuracy. AIM: To improve the classification performance of machine learning models identifying different types of prostate cancer tissue using a new dimensional reduction technique. APPROACH: A radial basis function (RBF) kernel support vector machine (SVM) model was trained on Raman spectra of prostate tissue from a 272-patient cohort (Centre hospitalier de l'Université de Montréal, CHUM) and tested on two independent cohorts of 76 patients [University Health Network (UHN)] and 135 patients (Centre hospitalier universitaire de Québec-Université Laval, CHUQc-UL). Two types of engineered features were used. Individual intensity features, i.e., Raman signal intensity measured at particular wavelengths and novel Raman spectra fitted peak features consisting of peak heights and widths. RESULTS: Combining engineered features improved classification performance for the three aforementioned classification tasks. The improvements for IDC-P/cancer classification for the UHN and CHUQc-UL testing sets in accuracy, sensitivity, specificity, and area under the curve (AUC) are (numbers in parenthesis are associated with the CHUQc-UL testing set): +4 % (+8 % ), +7 % (+9 % ), +2 % (6%), +9 (+9) with respect to the current best models. Discrimination between HGPIN and IDC-P was also improved in both testing cohorts: +2.2 % (+1.7 % ), +4.5 % (+3.6 % ), +0 % (+0 % ), +2.3 (+0). While no global improvements were obtained for the normal versus cancer classification task [+0 % (-2 % ), +0 % (-3 % ), +2 % (-2 % ), +4 (+3)], the AUC was improved in both testing sets. CONCLUSIONS: Combining individual intensity features and novel Raman fitted peak features, improved the classification performance on two independent and multicenter testing sets in comparison to using only individual intensity features.
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Carcinoma Intraductal não Infiltrante , Neoplasias da Próstata , Área Sob a Curva , Humanos , Aprendizado de Máquina , Masculino , Neoplasias da Próstata/diagnóstico por imagem , Análise Espectral RamanRESUMO
AIMS: We aimed to characterise a large cohort of non-invasive, human papillomavirus (HPV) and p53-independent verruciform lesions, such as 'vulvar acanthosis with altered differentiation' (VAAD), 'differentiated exophytic vulvar intra-epithelial lesion' (DEVIL) and 'verruciform lichen simplex chronicus' (vLSC). METHODS AND RESULTS: From January 2008 to December 2020 we retrospectively identified 36 eligible patients with verruciform non-invasive lesions (n = 36) and collected clinical, histological and follow-up parameters. Verruciform non-invasive lesions occurred at a median age of 71 years, with a median follow-up of 33.5 months. Clinically, pruritus was only reported in patients with VAAD (n = 3, 21%). Lesion colour was significantly different across categories (P = 0.028). Apart from the histopathological criteria already known to distinguish these entities (hypogranulosis, epithelial pallor and low-magnification architecture), no other significant criteria were discovered and significant overlap was observed, particularly between VAAD and DEVIL. Patients with vLSC trended towards longer survival without recurrence compared to VAAD and DEVIL (P = 0.082), but showed comparable invasion-free survival interval (P = 0.782). Squamous cell carcinomas (SCC) associated with either VAAD, DEVIL or vLSC displayed similar clinical, histopathological and biological parameters. In non-invasive precursor lesions, stromal oedema was associated with invasion (P = 0.015) and remained so upon Cox regression analysis (P = 0.009). CONCLUSION: Our study of HPV and p53 independent non-invasive verruciform lesions of the vulva highlights significant clinical, histopathological and biological overlap between VAAD, DEVIL and vLSC, suggesting that these pre-invasive lesions should be viewed as a spectrum. We also show that stromal features such as oedema might play an import role in progression to invasion.
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Carcinoma in Situ/patologia , Lesões Pré-Cancerosas/patologia , Neoplasias Vulvares/patologia , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Humanos , Pessoa de Meia-Idade , Estudos Retrospectivos , Proteína Supressora de Tumor p53Assuntos
Diferenciação Celular , Hamartoma/patologia , Nevo Pigmentado/patologia , Neoplasias Cutâneas/patologia , Adulto , Biomarcadores Tumorais/análise , Biópsia , Diagnóstico Diferencial , Feminino , Hamartoma/química , Hamartoma/cirurgia , Humanos , Imuno-Histoquímica , Nevo Pigmentado/química , Valor Preditivo dos Testes , Neoplasias Cutâneas/química , Neoplasias Cutâneas/cirurgiaRESUMO
BACKGROUND: Prostate cancer (PC) is the most frequently diagnosed cancer in North American men. Pathologists are in critical need of accurate biomarkers to characterize PC, particularly to confirm the presence of intraductal carcinoma of the prostate (IDC-P), an aggressive histopathological variant for which therapeutic options are now available. Our aim was to identify IDC-P with Raman micro-spectroscopy (RµS) and machine learning technology following a protocol suitable for routine clinical histopathology laboratories. METHODS AND FINDINGS: We used RµS to differentiate IDC-P from PC, as well as PC and IDC-P from benign tissue on formalin-fixed paraffin-embedded first-line radical prostatectomy specimens (embedded in tissue microarrays [TMAs]) from 483 patients treated in 3 Canadian institutions between 1993 and 2013. The main measures were the presence or absence of IDC-P and of PC, regardless of the clinical outcomes. The median age at radical prostatectomy was 62 years. Most of the specimens from the first cohort (Centre hospitalier de l'Université de Montréal) were of Gleason score 3 + 3 = 6 (51%) while most of the specimens from the 2 other cohorts (University Health Network and Centre hospitalier universitaire de Québec-Université Laval) were of Gleason score 3 + 4 = 7 (51% and 52%, respectively). Most of the 483 patients were pT2 stage (44%-69%), and pT3a (22%-49%) was more frequent than pT3b (9%-12%). To investigate the prostate tissue of each patient, 2 consecutive sections of each TMA block were cut. The first section was transferred onto a glass slide to perform immunohistochemistry with H&E counterstaining for cell identification. The second section was placed on an aluminum slide, dewaxed, and then used to acquire an average of 7 Raman spectra per specimen (between 4 and 24 Raman spectra, 4 acquisitions/TMA core). Raman spectra of each cell type were then analyzed to retrieve tissue-specific molecular information and to generate classification models using machine learning technology. Models were trained and cross-validated using data from 1 institution. Accuracy, sensitivity, and specificity were 87% ± 5%, 86% ± 6%, and 89% ± 8%, respectively, to differentiate PC from benign tissue, and 95% ± 2%, 96% ± 4%, and 94% ± 2%, respectively, to differentiate IDC-P from PC. The trained models were then tested on Raman spectra from 2 independent institutions, reaching accuracies, sensitivities, and specificities of 84% and 86%, 84% and 87%, and 81% and 82%, respectively, to diagnose PC, and of 85% and 91%, 85% and 88%, and 86% and 93%, respectively, for the identification of IDC-P. IDC-P could further be differentiated from high-grade prostatic intraepithelial neoplasia (HGPIN), a pre-malignant intraductal proliferation that can be mistaken as IDC-P, with accuracies, sensitivities, and specificities > 95% in both training and testing cohorts. As we used stringent criteria to diagnose IDC-P, the main limitation of our study is the exclusion of borderline, difficult-to-classify lesions from our datasets. CONCLUSIONS: In this study, we developed classification models for the analysis of RµS data to differentiate IDC-P, PC, and benign tissue, including HGPIN. RµS could be a next-generation histopathological technique used to reinforce the identification of high-risk PC patients and lead to more precise diagnosis of IDC-P.
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Carcinoma Intraductal não Infiltrante/diagnóstico por imagem , Aprendizado de Máquina/normas , Microscopia Óptica não Linear/normas , Neoplasias da Próstata/diagnóstico por imagem , Idoso , Canadá/epidemiologia , Carcinoma Intraductal não Infiltrante/epidemiologia , Carcinoma Intraductal não Infiltrante/patologia , Estudos de Casos e Controles , Estudos de Coortes , Humanos , Masculino , Pessoa de Meia-Idade , Microscopia Óptica não Linear/métodos , Neoplasias da Próstata/epidemiologia , Neoplasias da Próstata/patologia , Reprodutibilidade dos Testes , Estudos RetrospectivosRESUMO
Peritoneal keratin granulomatosis is a rare tumor-like lesion caused by deposition of tumor-produced keratin. It may be associated with endometrial or ovarian endometrioid adenocarcinoma, atypical polypoid adenomyoma of the endometrium, or ruptured mature teratomas of the ovary. We present 2 cases of peritoneal keratin granulomatosis associated with FIGO (International Federation of Gynecology and Obstetrics) stage 1 endometrial adenocarcinoma. This entity can mimic advanced-stage disease clinically and radiologically, as it did in those cases, and constitutes a diagnostic pitfall that pathologists and surgeons must be aware.