RESUMO
Endocervical adenocarcinomas (EACs) are a group of malignant neoplasms associated with diverse pathogenesis, morphology, and clinical behavior. As a component of the International Society of Gynecological Pathologists International Endocervical Adenocarcinoma Project, a large international retrospective cohort of EACs was generated in an effort to study potential clinicopathological features with prognostic significance that may guide treatment in these patients. In this study, we endeavored to develop a robust human papillomavirus (HPV)-associated EAC prognostic model for surgically treated International Federation of Gynecology and Obstetrics (FIGO) stage IA2 to IB3 adenocarcinomas incorporating patient age, lymphovascular space invasion (LVSI) status, FIGO stage, and pattern of invasion according to the Silva system (traditionally a 3-tier system). Recently, a 2-tier/binary Silva pattern of invasion system has been proposed whereby adenocarcinomas are classified into low-risk (pattern A/pattern B without LVSI) and high-risk (pattern B with LVSI/pattern C) categories. Our cohort comprised 792 patients with HPV-associated EAC. Multivariate analysis showed that a binary Silva pattern of invasion classification was associated with recurrence-free and disease-specific survival (P < 0.05) whereas FIGO 2018 stage I substages were not. Evaluation of the current 3-tiered system showed that disease-specific survival for those patients with pattern B tumors did not significantly differ from that for those patients with pattern C tumors, in contrast to that for those patients with pattern A tumors. These findings underscore the need for prospective studies to further investigate the prognostic significance of stage I HPV-associated EAC substaging and the inclusion of the binary Silva pattern of invasion classification (which includes LVSI status) as a component of treatment recommendations.
Assuntos
Adenocarcinoma , Infecções por Papillomavirus , Neoplasias do Colo do Útero , Adulto , Idoso , Feminino , Humanos , Pessoa de Meia-Idade , Adenocarcinoma/patologia , Adenocarcinoma/virologia , Adenocarcinoma/classificação , Ginecologia , Papillomavirus Humano/isolamento & purificação , Estadiamento de Neoplasias , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/patologia , Infecções por Papillomavirus/virologia , Infecções por Papillomavirus/diagnóstico , Patologistas , Prognóstico , Estudos Retrospectivos , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/virologia , Neoplasias do Colo do Útero/diagnóstico , Neoplasias do Colo do Útero/classificaçãoRESUMO
The three-tier (A vs. B vs. C) pattern-based (Silva) classification system is a strong and fairly reproducible predictor of the risk of lymph node involvement and recurrence of human papillomavirus (HPV)-associated endocervical adenocarcinoma (EA). Recently, a binary pattern-based classification system has been proposed which incorporates the Silva pattern and lymphovascular invasion (LVI) to assign tumors as "low risk" or "high risk" and this may have superior prognostic significance compared with the three-tier system as well as current International Federation of Gynecology and Obstetrics (FIGO) staging of cervix-confined disease. The interobserver reproducibility of this binary system, however, is unknown. Representative slides from 59 HPV-associated EAs (1-3 slides/case) were independently reviewed by 5 gynecologic pathologists who participated in an online training module before the study. In the first review, a pattern was assigned using the three-tier system. On the second review, a "low risk" or "high risk" designation was assigned and the presence or absence of LVI was specifically documented. Interobserver agreement was assessed using Fleiss' kappa. The binary system showed improved interobserver agreement (kappa=0.634) compared with the three-tier system (kappa=0.564), with a higher proportion of cases having agreement between at least 4/5 reviewers (86% vs. 73%). Nineteen and 8 cases showed improved and worse interobserver agreement using the binary system, respectively; the remainder showed no change. 3/5 reviewers showed no intraobserver discrepancy while the remaining 2 did in a small subset of cases (n=2 and 4, respectively). In this study, a binary pattern-based classification system showed improved interobserver agreement compared with the traditional three-tier system.
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Introduction. The identification of mitotic figures is essential for the diagnosis, grading, and classification of various different tumors. Despite its importance, there is a paucity of literature reporting the consistency in interpreting mitotic figures among pathologists. This study leverages publicly accessible datasets and social media to recruit an international group of pathologists to score an image database of more than 1000 mitotic figures collectively. Materials and Methods. Pathologists were instructed to randomly select a digital slide from The Cancer Genome Atlas (TCGA) datasets and annotate 10-20 mitotic figures within a 2â mm2 area. The first 1010 submitted mitotic figures were used to create an image dataset, with each figure transformed into an individual tile at 40x magnification. The dataset was redistributed to all pathologists to review and determine whether each tile constituted a mitotic figure. Results. Overall pathologists had a median agreement rate of 80.2% (range 42.0%-95.7%). Individual mitotic figure tiles had a median agreement rate of 87.1% and a fair inter-rater agreement across all tiles (kappa = 0.284). Mitotic figures in prometaphase had lower percentage agreement rates compared to other phases of mitosis. Conclusion. This dataset stands as the largest international consensus study for mitotic figures to date and can be utilized as a training set for future studies. The agreement range reflects a spectrum of criteria that pathologists use to decide what constitutes a mitotic figure, which may have potential implications in tumor diagnostics and clinical management.
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Neoplasias Ovarianas , Tumor de Células de Sertoli-Leydig , Tumores do Estroma Gonadal e dos Cordões Sexuais , Feminino , Masculino , Humanos , Tumor de Células de Sertoli-Leydig/genética , Neoplasias Ovarianas/genética , Hormônios , Ribonuclease III/genética , RNA Helicases DEAD-box/genéticaRESUMO
BACKGROUND: The pattern-based (Silva) classification of invasive human papilloma virus (HPV)-associated endocervical adenocarcinomas (HPVA) is an established and reproducible method to predict outcomes for this otherwise stage-dependent group of tumours. Previous studies utilising targeted sequencing have shown a correlation between mutational profiles and an invasive pattern. However, such correlation has not been explored using comprehensive molecular testing. DESIGN: Clinicopathologic data including invasive pattern (Silva groups A, B, and C) was collected for a cohort of invasive HPVA, which previously underwent massive parallel sequencing using a panel covering 447 genes. Pathogenic alterations, molecular signatures, tumour mutational burden (TMB), and copy number alterations (CNA) were correlated with pattern of invasion. RESULTS: Forty five HPVA (11 pattern A, 17 pattern B, and 17 pattern C tumours) were included. Patients with pattern A presented at stage I with no involved lymph nodes or evidence of recurrence (in those with >2 months of follow-up). Patterns B and C patients also mostly presented at stage I with negative lymph nodes, but had a greater frequency of recurrence; 3/17 pattern B and 1/17 pattern C HPVAs harboured lymphovascular space invasion (LVI). An APOBEC mutational signature was detected only in Silva pattern C tumours (5/17), and pathogenic PIK3CA changes were detected only in destructively invasive HPVA (patterns B and C). When cases were grouped as low-risk (pattern A and pattern B without LVI) and high-risk (pattern B with LVI and pattern C), high-risk tumours were enriched in mutations in PIK3CA, ATRX, and ERBB2. There was a statistically significant difference in TMB between low-risk and high-risk pattern tumours (P = 0.006), as well as between Pattern C tumours with and without an APOBEC signature (P = 0.002). CNA burden increased from pattern A to C. CONCLUSION: Our findings further indicate that key molecular events in HPVA correlate with the morphologic invasive properties of the tumour and their aggressiveness. Pattern B tumours with LVI clustered with pattern C tumours, whereas pattern B tumours without LVI approached pattern A genotypically. Our study provides a biologic foundation for consolidating the Silva system into low-risk (pattern A + B without LVI) and high-risk (pattern B with LVI and pattern C) categories.
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Adenocarcinoma , Infecções por Papillomavirus , Neoplasias do Colo do Útero , Feminino , Humanos , Papillomavirus Humano , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/patologia , Adenocarcinoma/genética , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/patologia , Biomarcadores Tumorais , Prognóstico , Invasividade NeoplásicaRESUMO
BACKGROUND: In this study, the authors sought to describe the cytologic features of primary gynecologic germ cell tumors and carcinomas exhibiting germ cell differentiation because little information currently exists. METHODS: An institutional database search was performed to identify histologically confirmed gynecologic germ cell tumors and carcinomas with germ cell tumor differentiation. Available cytologic material was reviewed by three observers, and morphologic features were recorded in addition to patient age at original diagnosis, primary tumor site, site(s) from which the examined cytologic material was obtained, and the type of examined cytologic preparations. RESULTS: In total, 15 cytologic specimens from 12 women (aged 19-82 years) were identified and included touch preparations of core biopsies from various sites (n = 6), fine-needle biopsies (n = 2), pelvic washings (n = 1), ascitic fluids (n = 4), pelvic cyst fluid (n = 1), and endometrial aspirate (n = 1). Of the 12 patients, seven had primary gynecologic germ cell tumors, four had gynecologic (ovarian and endometrial) tumors exhibiting somatic yolk sac tumor-like differentiation, and the remaining patient had an intestinal-type adenocarcinoma arising within an ovarian teratoma. There was morphologic overlap among many of the cases, although cytoplasmic vacuolation/granular cytoplasm was seen in 75% of primary yolk sac tumors or carcinomas with yolk sac tumor differentiation, and dense/squamoid cytoplasm was seen in 100% of teratomatous elements that were sampled. CONCLUSIONS: Germ cell tumors and somatic neoplasms exhibiting germ cell tumor differentiation occurring in adult women share some cytologic features and may be difficult to distinguish from one another, although some tumor types showed characteristic cytomorphologic findings.
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Adenocarcinoma , Tumor do Seio Endodérmico , Neoplasias Embrionárias de Células Germinativas , Neoplasias Ovarianas , Teratoma , Adulto , Humanos , Feminino , Tumor do Seio Endodérmico/patologia , Neoplasias Embrionárias de Células Germinativas/diagnóstico , Teratoma/patologia , Neoplasias Ovarianas/diagnóstico , Adenocarcinoma/patologiaRESUMO
Introduction: Mutations in the TP53 gene are indicative of worse outcome in bladder cancer and are usually assessed by immunohistochemistry. To define p53-overexpression, a threshold of >10% is most commonly used (cut-off1). Recently, a novel cut-off (aberrant = 0% or ≥50%) (cut-off2) showed better correlation to clinical outcome. In this study, we evaluate the association between p53-immunohistochemistry cut-offs, clinico-pathological variables and disease-specific survival (DSS). Methods: Seven-hundred-fifty chemotherapy-naïve patients who underwent radical cystectomy were included (92% muscle-invasive bladder cancer. In addition to cut-off1 and cut-off2, a third cut-off (cut-off3) was determined based on the highest Youden-index value. Cut-off values were associated with clinico-pathological variables and FGFR3 mutation status. The Kaplan-Meier method was used to estimate DSS. Results: Aberrant p53-expression was found in 489 (65%) (cut-off1) and 466 (62%) (cut-off2) tumors. Cut-off3 was determined at 25% and aberrant p53-expression in 410 cases (55%) (cutoff3). p53-expression levels were significantly associated with higher pT-stage (cut-off1/2/3: P = 0.047, P = 0.006 and P = 0.0002, respectively), higher grade (all, P < 0.0001), and FGFR3 wild-type (cut-off1: P = 0.02, cut-offs2&3: P = 0.001). Median follow-up was 5.3 years (interquartile range, 4.0-6.0 years). p53-expression was not associated with DSS for any of the three cut-offs (cut-off1/2/3: P-log-rank = 0.566, 0.77 and 0.50, respectively). If we only considered locally advanced bladder cancer, results on DSS remained non-significant. Conclusion: This multi-center, multi-laboratory study showed that, regardless of the cut-off used, p53-immunohistochemistry did not enable selection of patients with worse outcome. Our results suggest that p53-immunohistochemistry alone is not suitable to guide clinical decision making after radical cystectomy.
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Proteína Supressora de Tumor p53 , Neoplasias da Bexiga Urinária , Humanos , Proteína Supressora de Tumor p53/genética , Genes p53 , Imuno-Histoquímica , Neoplasias da Bexiga Urinária/diagnóstico , Neoplasias da Bexiga Urinária/cirurgia , Neoplasias da Bexiga Urinária/genética , Prognóstico , Cistectomia , Estudos RetrospectivosRESUMO
BACKGROUND: Cytologic specimens often represent the initial diagnostic material for tubo-ovarian neoplasms resulting from therapeutic paracentesis for patients presenting with high-volume ascites. However, subtyping and immunohistochemical (IHC) characterization, which have implications in preoperative management and downstream ancillary testing, are not routinely performed in many institutions. This study aims to perform cytohistologic correlation of commonly used IHC stains to establish their reliability in peritoneal fluids/washing specimens. METHODS: A retrospective search of the laboratory information systems was performed to identify peritoneal fluid/washing specimens involved by borderline or malignant epithelial tubo-ovarian neoplasms and concurrent/subsequent surgical resection specimens. Cell blocks and tissue were stained for PAX8, WT-1, p53, p16, Napsin-A, estrogen receptor, and progesterone receptor, and staining between cytological and surgical specimens was compared. RESULTS: A total of 56 case pairs were included, with the following final diagnoses on histological examination: 37 high-grade serous carcinomas, eight clear cell carcinomas, one endometrioid adenocarcinoma, two low-grade serous carcinomas, and eight serous borderline tumors. There was perfect cytohistologic correlation for PAX8 (Lin's concordance correlation coefficient [LINCCC] = 1.00) and WT-1 (LINCCC = 1.00), substantial/good correlation for p53 (LINCCC = 0.96), p16 (LINCCC = 0.93), napsin-A (LINCCC = 0.91) and ER (LINCCC = 0.77), and moderate correlation for PR (LINCCC = 0.54). CONCLUSIONS: Immunohistochemical correlation between peritoneal fluid and surgical resection specimens for tubo-ovarian neoplasms is high. Common subtypes of tubo-ovarian carcinomas can be reliably distinguished on fluids using IHC.
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Carcinoma , Cistadenocarcinoma Seroso , Neoplasias Ovarianas , Humanos , Feminino , Proteína Supressora de Tumor p53 , Estudos Retrospectivos , Reprodutibilidade dos Testes , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/cirurgia , Neoplasias Ovarianas/patologia , Cistadenocarcinoma Seroso/diagnóstico , Cistadenocarcinoma Seroso/cirurgia , Biomarcadores TumoraisRESUMO
OBJECTIVE: We sought to describe clinicopathologic and treatment factors associated with oncologic outcomes in patients with early-stage ovarian clear cell carcinoma undergoing complete staging and in a sub-set of these patients undergoing fertility-conserving surgery. METHODS: We retrospectively identified patients with ovarian clear cell carcinoma initially treated at our institution from January 1, 1996 to March 31, 2020. Survival was estimated using Kaplan-Meier curves and compared by log-rank test. Survival-associated variables were identified by Cox proportional hazards regression. RESULTS: Of 182 patients, mismatch repair and p53 protein expression were assessed by immunohistochemistry on 82 and 66 samples, respectively. There were no significant differences in progression-free survival or overall survival between mismatch repair-deficient (n=6, including 4 patients with Lynch syndrome; 7.3%) and mismatch repair-proficient patients, whereas aberrant p53 expression (n=3; 4.5%) was associated with worse progression-free (p<0.001) and overall survival (p=0.01). Patients with stage IA/IC1 disease had a 95% 5-year overall survival rate (95% CI 88% to 98%); patients with stage IC2/IC3 disease had a similar 5-year overall survival rate (76%; 95% CI 54% to 88%) to that of patients with stage IIA/IIB disease (82%; 95% CI 54% to 94%). There was no difference in 5-year overall survival in patients with stage IA/IC1 undergoing chemotherapy versus observation (94% vs 100%). Nine patients underwent fertility-sparing surgery and none experienced recurrence. Of five patients who pursued fertility, all had successful pregnancies. CONCLUSIONS: In patients with completely staged ovarian clear cell carcinoma, those with stage IA/IC1 disease have an excellent prognosis, regardless of chemotherapy. Aberrant p53 expression may portend worse outcomes. Additional investigation is warranted on the safety of fertility conservation in patients with stage IA/IC1 disease.
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Carcinoma , Preservação da Fertilidade , Neoplasias Ovarianas , Gravidez , Feminino , Humanos , Neoplasias Ovarianas/cirurgia , Neoplasias Ovarianas/tratamento farmacológico , Proteína Supressora de Tumor p53 , Estudos Retrospectivos , Estadiamento de Neoplasias , Carcinoma/patologia , Medição de RiscoRESUMO
Tumor inflammation is prognostically significant in high-grade muscle-invasive bladder cancer (MIBC). However, the underlying mechanisms remain elusive. To identify inflammation-associated immune gene expression patterns, we performed transcriptomic profiling of 40 MIBC archival tumors using the NanoString nCounter Human v.1.1 PanCancer Panel. Findings were validated using the TCGA MIBC dataset. Unsupervised and supervised clustering identified a distinctive immune-related gene expression profile for inflammation, characterized by significant upregulation of 149 genes, particularly chemokines, a subset of which also had potential prognostic utility. Some of the most enriched biological processes were lymphocyte activation and proliferation, leukocyte adhesion and migration, antigen processing and presentation and cellular response to IFN-γ. Upregulation of numerous IFN-γ-inducible chemokines, class II MHC molecules and immune checkpoint genes was detected as part of the complex immune response to MIBC. Further, B-cell markers linked to tertiary lymphoid structures were upregulated, which in turn is predictive of tumor response to immunotherapy and favorable outcome. Our findings of both an overall activated immune profile and immunosuppressive microenvironment provide novel insights into the complex immune milieu of MIBC with inflammation and supports its clinical significance for predicting prognosis and immunotherapeutic responsiveness, which warrants further investigation. This may open novel opportunities to identify mechanisms for developing new immunotherapeutic strategies.
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Quimiocinas/imunologia , Quimiocinas/metabolismo , Perfilação da Expressão Gênica , Imunoterapia , Interferon gama/genética , Interferon gama/imunologia , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/imunologia , Neoplasias da Bexiga Urinária/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Inflamação , Interferon gama/metabolismo , Ativação Linfocitária , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Transcriptoma , Microambiente Tumoral/imunologia , Regulação para Cima/genética , Neoplasias da Bexiga Urinária/patologiaRESUMO
Ovarian metastases from endocervical adenocarcinomas (EAs) are rare but well-described. Silva Pattern A tumors have been reported to pose essentially no risk of lymph node metastases or recurrence. We describe a cohort of patients with Silva Pattern A EAs with ovarian metastases, as well as involvement of other sites. Eight pattern A EAs with ovarian metastases (4 synchronous, 4 metachronous) were identified from our institution's pathologic archives (2008-2021). Clinicopathologic and molecular features for each case were recorded. All patients were treated by hysterectomy; in each case, the entire tumor was submitted for histologic evaluation. The synchronous metastases were all clinically suspected to be ovarian primary tumors; EAs with metachronous ovarian involvement were confined to the uterus at initial diagnosis, with ovarian metastasis occurring 5 to 171 months after hysterectomy. Morphologically, all tumors were predominantly gland-forming, 5/8 (63%) displayed prominent mucinous differentiation, and 5/8 (63%) involved the corpus. All EAs were either noninvasive (exophytic/papillary/more complex than adenocarcinoma in situ) or showed nondestructive cervical stromal invasion to a depth of 5 mm or less. In the 5 tumors tested by next-generation sequencing, ARID1A, GNAS, and KRAS mutations were detected in 2 (40%), 3 (60%), and 4 (80%) cases, respectively. All 6 patients with follow-up (range, 32 to 181 mo; median, 99.5 mo) had at least 1 recurrence. All but one are without evident disease at last clinical assessment. In an otherwise typical Silva Pattern A EA, corpus involvement, mucinous differentiation, and certain gene mutations may be associated with risk for synchronous or metachronous ovarian metastases.
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Adenocarcinoma , Carcinoma , Tumor de Krukenberg , Neoplasias Ovarianas , Neoplasias do Colo do Útero , Adenocarcinoma/diagnóstico , Feminino , Humanos , Neoplasias Ovarianas/patologia , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/patologiaRESUMO
AIMS: To assess the utility of a three-antibody immunohistochemistry panel to classify muscle invasive bladder cancers (MIBCs) in correlation with morphological features and p53 status. METHODS: A retrospective review of 243 chemotherapy naïve MIBC cystectomy specimens was performed to assess morphological features. A tissue microarray was sequentially stained with CK5/6, GATA-3 and p16. Subgroups were assigned as basal-like (CK5/6+, GATA3-) and luminal (CK5/6-, GATA3+), with the latter subdivided into genomically unstable (GU, p16+) and urothelial like (Uro, p16-) subgroups. p53 staining was assessed as abnormal/wild type. Cases from the The Cancer Genome Atlas (TCGA) portal were assessed as external validation. RESULTS: We identified 78.8% luminal, 21.2% basal cases within our cohort and 63.4% luminal, 36.6% basal in the TCGA dataset. Divergent differentiation (p<0.001) was significantly associated with basal-subtype cases in both cohorts. Within the luminal subgroup (n=186), 81 cases were classified as GU and 105 as Uro. Abnormal p53 staining was noted in 48.0% of basal, 80.2% GU and 38.1% Uro cases. Further, basal-subtype tumours significantly correlated with disease-specific death compared with Uro cases in multivariate survival analysis. CONCLUSIONS: This retrospective study demonstrates the potential utility of a three-antibody immunohistochemistry panel to differentiate luminal and basal MIBC.
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Carcinoma de Células de Transição , Neoplasias da Bexiga Urinária , Humanos , Biomarcadores Tumorais/genética , Carcinoma de Células de Transição/diagnóstico , Carcinoma de Células de Transição/genética , Músculos/patologia , Prognóstico , Estudos Retrospectivos , Proteína Supressora de Tumor p53/genética , Neoplasias da Bexiga Urinária/diagnóstico , Neoplasias da Bexiga Urinária/genéticaRESUMO
STK11 encodes for the protein liver kinase B1, a serine/threonine kinase which is involved in a number of physiological processes including regulation of cellular metabolism, cell polarity and the DNA damage response. It acts as a tumour suppressor via multiple mechanisms, most classically through AMP-activated protein kinase-mediated inhibition of the mammalian target of rapamycin signalling pathway. Germline loss-of-function mutations in STK11 give rise to Peutz-Jeghers syndrome, which is associated with hamartomatous polyps of the gastrointestinal tract, mucocutaneous pigmentation and a substantially increased lifetime risk of many cancers. In the sporadic setting, STK11 mutations are commonly seen in a subset of adenocarcinomas of the lung in addition to a number of other tumours occurring at various sites. Mutations in STK11 have been associated with worse prognoses across a range of malignancies and may be a predictor of poor response to immunotherapy in a subset of lung cancers, though further studies are needed before the presence of STK11 mutations can be implemented as a routine clinical biomarker.
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Mutação , Neoplasias/genética , Síndrome de Peutz-Jeghers/genética , Proteínas Serina-Treonina Quinases , Quinases Proteína-Quinases Ativadas por AMP , Humanos , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Serina-Treonina Quinases/fisiologiaAssuntos
Biomarcadores Tumorais/genética , Fusão Gênica , Coativador 2 de Receptor Nuclear/genética , Neoplasias Ovarianas/genética , Tumor Rabdoide/genética , Tumores do Estroma Gonadal e dos Cordões Sexuais/genética , Neoplasias Uterinas/genética , Adulto , Biomarcadores Tumorais/análise , Feminino , Predisposição Genética para Doença , Humanos , Neoplasias Ovarianas/química , Neoplasias Ovarianas/patologia , Fenótipo , Tumor Rabdoide/química , Tumor Rabdoide/patologia , Tumor Rabdoide/cirurgia , Tumores do Estroma Gonadal e dos Cordões Sexuais/química , Tumores do Estroma Gonadal e dos Cordões Sexuais/patologia , Resultado do Tratamento , Neoplasias Uterinas/química , Neoplasias Uterinas/patologia , Neoplasias Uterinas/cirurgiaRESUMO
Fumarate hydratase (FH), encoded by the FH gene, is an enzyme which catalyses the conversion of fumarate to L-malate as part of the tricarboxylic acid cycle. Biallelic germline mutations in FH result in fumaric aciduria, a metabolic disorder resulting in severe neurological and developmental abnormalities. Heterozygous germline mutations in FH result in hereditary leiomyomatosis and renal cell carcinoma, a cancer predisposition syndrome. FH deficiency has multiple oncogenic mechanisms including through promotion of aerobic glycolysis, induction of pseudohypoxia, post-translational protein modification and impairment of DNA damage repair by homologous recombination. FH-deficient neoplasms can present with characteristic morphological features that raise suspicion for FH alterations and also frequently demonstrate loss of FH immunoreactivity and intracellular accumulation of 2-succinocysteine, also detected by immunohistochemistry.
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Fumarato Hidratase/deficiência , Fumarato Hidratase/metabolismo , Erros Inatos do Metabolismo/enzimologia , Hipotonia Muscular/enzimologia , Neoplasias/enzimologia , Transtornos Psicomotores/enzimologia , Animais , Fumarato Hidratase/genética , Regulação Enzimológica da Expressão Gênica , Predisposição Genética para Doença , Humanos , Leiomiomatose/enzimologia , Leiomiomatose/genética , Leiomiomatose/patologia , Erros Inatos do Metabolismo/genética , Hipotonia Muscular/genética , Mutação , Neoplasias/genética , Neoplasias/patologia , Síndromes Neoplásicas Hereditárias/enzimologia , Síndromes Neoplásicas Hereditárias/genética , Síndromes Neoplásicas Hereditárias/patologia , Fenótipo , Transtornos Psicomotores/genética , Neoplasias Cutâneas/enzimologia , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Neoplasias Uterinas/enzimologia , Neoplasias Uterinas/genética , Neoplasias Uterinas/patologiaRESUMO
PURPOSE OF REVIEW: Uterine sarcomas are rare and are often challenging to differentiate on imaging from benign mimics, such as leiomyoma. As functional MRI techniques have improved and new adjuncts, such as machine learning and texture analysis, are now being investigated, it is helpful to be aware of the current literature on imaging features that may sometimes allow for preoperative distinction. RECENT FINDINGS: MRI, with both conventional and functional imaging, is the modality of choice for evaluating uterine mesenchymal tumors, especially in differentiating uterine leiomyosarcoma from leiomyoma through validated diagnostic algorithms. MRI is sometimes helpful in differentiating high-grade stromal sarcoma from low-grade stromal sarcoma or differentiating endometrial stromal sarcoma from endometrial carcinoma. However, imaging remains nonspecific for evaluating rarer neoplasms, such as uterine tumor resembling ovarian sex cord tumor or perivascular epithelioid cell tumor, primarily because of the small number and power of relevant studies. SUMMARY: Through advances in MRI techniques and novel investigational imaging adjuncts, such as machine learning and texture analysis, imaging differentiation of malignant from benign uterine mesenchymal tumors has improved and could help reduce morbidity relating to misdiagnosis or diagnostic delays.
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Neoplasias do Endométrio , Sarcoma do Estroma Endometrial , Sarcoma , Neoplasias Uterinas , Feminino , Humanos , Imageamento por Ressonância Magnética , Sarcoma/diagnóstico por imagem , Neoplasias Uterinas/diagnóstico por imagemRESUMO
â¢In a bleeding postmenopausal woman with didelphys uterus, endometrial biopsy should be taken from both uterine cavities.â¢Sentinel lymph node mapping has not been previously described in the setting of endometrial cancer and uterine didelphys.â¢Routine sentinel lymph node mapping was successfully performed in a patient with endometrial cancer and uterine didelphys.
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The NTRK genes (NTRK1, NTRK2, and NTRK3) encode for TrkA, TrkB, and TrkC, neurotrophic tyrosine receptor kinases which serve a variety of functions including in the regulation of pathways involved in carcinogenesis. A number of reports have described NTRK gene fusions in a variety of adult and pediatric tumor types from various organ systems including the central nervous system, thyroid gland, breast, and soft tissue. NTRK-rearranged uterine sarcomas are a recently described group of tumors which occur in both the uterine corpus and cervix, tend to morphologically resemble fibrosarcoma, and may behave aggressively, although data is limited given the newly recognized nature and thus relative rarity of these tumors. Herein, we present the case of a cervical sarcoma with SPECC1L-NTRK3 fusion (detected with Illumina RNA Fusion Panel), prospectively diagnosed at the time of cervical biopsy and subsequently treated with hysterectomy. The clinical presentation, radiologic findings, morphologic features, and immunohistochemical profile of this case will be reviewed and compared with the body of existing literature to date. Identification of NTRK-rearranged neoplasms is important as targeted therapy in the form of NTRK inhibitors has recently become widely available.
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Fibrossarcoma/diagnóstico , Glicoproteínas de Membrana/genética , Receptor trkA/genética , Receptor trkB/genética , Receptor trkC/genética , Sarcoma/diagnóstico , Neoplasias de Tecidos Moles/diagnóstico , Neoplasias Uterinas/diagnóstico , Colo do Útero/patologia , Colo do Útero/cirurgia , Feminino , Fibrossarcoma/patologia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Histerectomia , Glicoproteínas de Membrana/metabolismo , Receptor trkA/metabolismo , Receptor trkB/metabolismo , Receptor trkC/metabolismo , Sarcoma/patologia , Sarcoma/cirurgia , Neoplasias de Tecidos Moles/patologia , Neoplasias de Tecidos Moles/cirurgia , Neoplasias Uterinas/patologia , Neoplasias Uterinas/cirurgiaRESUMO
Ovarian carcinoma with a somatically derived yolk sac tumor component is a phenomenon known to mostly occur in postmenopausal women. Herein, we report an ovarian endometriosis-associated somatic yolk sac tumor arising in the background of a low-grade endometrioid adenocarcinoma in a young woman. A 27-yr-old woman presented with abdominal pain, subsequently recognized to be caused by a right ovarian mass undergoing torsion. Following operative management, microscopic examination of the salpingo-oophorectomy specimen showed endometriosis and a predominantly cystic ovarian neoplasm with 2 distinct phenotypic areas: (1) a yolk sac tumor component containing Schiller-Duval bodies and (2) a low-grade endometrioid carcinoma component with squamous metaplasia. Immunohistochemical evaluation showed distinct profiles in the yolk sac tumor (estrogen receptor/progesterone receptor/PAX8 negative, SALL4/Glypican 3 positive) and endometrioid (estrogen receptor/progesterone receptor/PAX8 positive, SALL4/Glypican 3 negative) components. Given these findings, the diagnosis of an endometriosis-associated endometrioid adenocarcinoma with a somatically derived yolk sac tumor was rendered. The tumor was staged as pT1c1 due to intraoperative spillage. The patient underwent chemotherapeutic treatment and after 15 mo of follow-up, she was alive with no evidence of recurrence. This example demonstrates that somatic yolk sac tumor differentiation in ovarian epithelial neoplasia can occur in young patients; awareness of this phenomenon is important as somatic and germ cell yolk sac neoplasia have different behavior and therapy.