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Clear cell ovarian carcinoma (CCOC) is an aggressive malignancy affecting younger women. Despite ovarian cancer subtypes having diverse molecular and clinical characteristics, the mainstay of treatment for advanced stage disease remains cytotoxic chemotherapy. Late stage CCOC is resistant to conventional chemotherapy, which means a suboptimal outcome for patients affected. Despite detailed genomic, epigenomic, transcriptomic, and proteomic characterisation, subtype-specific treatment for CCOC has shown little progress. The unique glycogen accumulation defining CCOC suggests altered metabolic pathway activity and dependency. This study presents the first metabolomic landscape of ovarian cancer subtypes, including 42 CCOC, 20 high-grade serous and 21 endometrioid ovarian carcinomas, together comprising the three most common ovarian carcinoma subtypes. We describe a distinct metabolomic landscape of CCOC compared with other ovarian cancer subtypes, including alterations in energy utilisation and cysteine metabolism. In addition, we identify CCOC-specific alterations in metabolic pathways including serine biosynthesis and ROS-associated pathways that could serve as potential therapeutic targets. Our study provides the first in-depth study into the metabolome of ovarian cancers and a rich resource to support ongoing research efforts to identify subtype-specific therapeutic targets that could improve the dismal outcome for patients with this devastating malignancy. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
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Adenocarcinoma de Células Claras , Metaboloma , Neoplasias Ovarianas , Feminino , Humanos , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/genética , Adenocarcinoma de Células Claras/metabolismo , Adenocarcinoma de Células Claras/patologia , Adenocarcinoma de Células Claras/genética , Pessoa de Meia-Idade , Metabolômica/métodos , Idoso , Adulto , Redes e Vias MetabólicasRESUMO
Low-grade serous ovarian carcinoma (LGSC) is a rare and lethal subtype of ovarian cancer. LGSC is pathologically, biologically, and clinically distinct from the more common high-grade serous ovarian carcinoma (HGSC). LGSC arises from serous borderline ovarian tumours (SBTs). The mechanism of transformation for SBTs to LGSC remains poorly understood. To better understand the biology of LGSC, we performed whole proteome profiling of formalin-fixed, paraffin-embedded tissue blocks of LGSC (n = 11), HGSC (n = 19), and SBTs (n = 26). We identified that the whole proteome is able to distinguish between histotypes of the ovarian epithelial tumours. Proteins associated with the tumour microenvironment were differentially expressed between LGSC and SBTs. Fibroblast activation protein (FAP), a protein expressed in cancer-associated fibroblasts, is the most differentially abundant protein in LGSC compared with SBT. Multiplex immunohistochemistry (IHC) for immune markers (CD20, CD79a, CD3, CD8, and CD68) was performed to determine the presence of B cells, T cells, and macrophages. The LGSC FAP+ stroma was associated with greater abundance of Tregs and M2 macrophages, features not present in SBTs. Our proteomics cohort reveals that there are changes in the tumour microenvironment in LGSC compared with its putative precursor lesion, SBT. These changes suggest that the tumour microenvironment provides a supportive environment for LGSC tumourigenesis and progression. Thus, targeting the tumour microenvironment of LGSC may be a viable therapeutic strategy. © 2024 The Pathological Society of Great Britain and Ireland.
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Cistadenocarcinoma Seroso , Neoplasias Ovarianas , Microambiente Tumoral , Humanos , Feminino , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/genética , Cistadenocarcinoma Seroso/patologia , Cistadenocarcinoma Seroso/metabolismo , Biomarcadores Tumorais/metabolismo , Biomarcadores Tumorais/genética , Gradação de Tumores , Progressão da Doença , Proteômica/métodos , Serina Endopeptidases/metabolismo , Serina Endopeptidases/genética , Pessoa de Meia-Idade , Proteínas de Membrana/metabolismo , Gelatinases/metabolismo , Idoso , Endopeptidases/metabolismo , Fibroblastos Associados a Câncer/metabolismo , Fibroblastos Associados a Câncer/patologia , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/patologia , Linfócitos do Interstício Tumoral/metabolismoRESUMO
Objective: Serous tubal intraepithelial carcinoma (STIC) are precursors for high grade serous carcinomas (HGSC) of tubo-ovarian origin. It is a rare entity, most commonly described in patients with a BRCA pathogenic variant (PV) undergoing risk-reducing surgery. Little is known about the risk of subsequent HGSC in patients found to have an isolated STIC without a genetic PV. The objective of this study is to report the outcomes of STIC diagnosed in patients with negative genetic testing ("average risk"). Methods: Retrospective population-based cohort study from British Columbia, Canada. Chart review of patients diagnosed with an isolated STIC from January 2012 to May 2022. Average risk patients are defined as individuals with known negative genetic testing results. Treatment and outcomes are described in the "average risk", BRCA PV, and total cohorts. Results: Twenty-nine patients with isolated STIC were identified. Ten patients had a BRCA PV, four had other variants identified (BRIP1, MLH1, BRIP1 VUS, BRCA 2 VUS), nine had no PV identified ("average risk"), and six were unknown (no genetic testing). Of the nine "average risk" patients, eight (89%) underwent surgical staging. Three (33.3%) had subsequent HGSC diagnosed 29, 70 and 86 months after STIC diagnosis. Conclusions: STIC identified in patients with negative genetic testing are at risk of subsequent HGSC. Patients developed primary peritoneal HGSC despite surgical staging. These patients should also be included in future meta-analysis to determine outcomes and optimal treatment.
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We compared grading systems and examined associations with tumor stroma and survival in patients with cervical squamous cell carcinoma. Available tumor slides were collected from 10 international institutions. Broders tumor grade, Jesinghaus grade (informed by the pattern of tumor invasion), Silva pattern, and tumor stroma were retrospectively analyzed; associations with overall survival (OS), progression-free survival (PFS), and presence of lymph node metastases were examined. Binary grading systems incorporating tumor stromal changes into Broders and Jesinghaus grading systems were developed. Of 670 cases, 586 were reviewed for original Broders tumor grade, 587 for consensus Broders grade, 587 for Jesinghaus grade, 584 for Silva pattern, and 556 for tumor stroma. Reproducibility among grading systems was poor (κ = 0.365, original Broders/consensus Broders; κ = 0.215, consensus Broders/Jesinghaus). Median follow-up was 5.7 years (range, 0-27.8). PFS rates were 93%, 79%, and 71%, and OS rates were 98%, 86%, and 79% at 1, 5, and 10 years, respectively. On univariable analysis, original Broders ( P < 0.001), consensus Broders ( P < 0.034), and Jesinghaus ( P < 0.013) grades were significant for OS; original Broders grade was significant for PFS ( P = 0.038). Predictive accuracy for OS and PFS were 0.559 and 0.542 (original Broders), 0.542 and 0.525 (consensus Broders), 0.554 and 0.541 (Jesinghaus grade), and 0.512 and 0.515 (Silva pattern), respectively. Broders and Jesinghaus binary tumor grades were significant on univariable analysis for OS and PFS, and predictive value was improved. Jesinghaus tumor grade ( P < 0.001) and both binary systems (Broders, P = 0.007; Jesinghaus, P < 0.001) were associated with the presence of lymph node metastases. Histologic grade has poor reproducibility and limited predictive accuracy for squamous cell carcinoma. The proposed binary grading system offers improved predictive accuracy for survival and the presence of lymph none metastases.
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Vulvovaginal melanoma (VVM) is a rare but deadly disease, accounting for 5% of all vulvar malignancies, with a 5-yr survival rate of only 47% for all stages of the disease. VVM is a distinct subset of melanoma, with a unique genomic profile and underlying pathogenesis unassociated with sun exposure. Distinguishing these rare malignancies from very common pigmented lesions of the vulva and vagina is challenging as histologic features often overlap between entities. PReferentially expressed Antigen in MElanoma (PRAME) is a melanoma-associated protein, and immunohistochemistry (IHC) for PRAME distinguishes cutaneous, oral mucosal, and retinal melanoma from atypical nevi. Given the biological differences between VVM and cutaneous melanoma, the utility of PRAME IHC for the diagnosis of VVM is unknown. We accrued a cohort of 20 VVM and 21 benign vulvar melanocytic nevi. We found that nuclear PRAME IHC staining with 4+ intensity was present in 85% of the VVM and 0% of the nevi. With the assistance of PRAME IHC, we found evidence of close or positive margin involvement in 3 of 10 cases where margins were originally diagnosed as negative for melanoma in situ. Our study is the first to assess PRAME IHC in a cohort of VVM cases and provides confidence for using PRAME IHC to assist with diagnosis and margin assessment in this rare disease.
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We aimed to determine the frequency of human papillomavirus-independent (HPVI) cervical squamous cell carcinoma (SCC) and to describe clinicopathologic characteristics. Among 670 patients with surgically treated SCCs in an established multi-institutional cohort, 447 had available tissue. Tissue microarrays were constructed and studied by in situ hybridization (ISH) for high-risk and low-risk human papillomavirus (HPV) mRNA and immunohistochemistry for p16 and p53. Tumors were HPVI if negative by HPV ISH and they failed to show diffuse p16 positivity by immunohistochemistry, and human papillomavirus-associated (HPVA) if positive by HPV ISH. Ten HPVI SCCs and 435 HPVA SCCs were identified; 2 cases were equivocal and excluded from analysis. The overall rate of HPVI SCC was low (2%) but was higher among older patients (7% in patients above 60 y of age and 17% in patients above 70 y of age). Compared with HPVA, patients with HPVI SCC were significantly older (median age, 72 vs. 49, P <0.001) and diagnosed at a higher stage (40% vs. 18% with stage III/IV disease, P =0.055). p53 expression was varied; 2 cases (20%) had null expression and 8 (80%) had wild-type expression. HPVI SCCs were heterogenous, with keratinizing, nonkeratinizing, and warty morphologies observed. Several cases had a precursor lesion reminiscent of differentiated vulvar intraepithelial neoplasia, with prominent basal atypia and hypereosinophilia or a basaloid-like morphology. Two patients (20%) had distant recurrences within 12 months, and 3 (30%) died of disease during follow-up. HPVI SCCs are rare tumors that are more common among older patients with higher stage disease and have important clinical and histologic differences from HPVA SCCs.
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Carcinoma de Células Escamosas , Papiloma , Infecções por Papillomavirus , Neoplasias do Colo do Útero , Feminino , Humanos , Idoso , Papillomavirus Humano , Infecções por Papillomavirus/patologia , Colo do Útero/química , Carcinoma de Células Escamosas/patologia , Incidência , Proteína Supressora de Tumor p53/análise , Neoplasias do Colo do Útero/patologia , Papillomaviridae/genética , Inibidor p16 de Quinase Dependente de Ciclina/análiseRESUMO
OBJECTIVE: We evaluated clinicopathologic parameters of patients with cervical squamous cell carcinoma (SCC) who were treated with initial surgical management and assessed their relation to survival outcomes. Specifically, we evaluated the relation between extent of lymphovascular invasion (LVI) and survival outcomes. METHODS: All available tumor slides from patients with initially surgically treated cervical SCC were collected from 10 institutions and retrospectively analyzed. Standard clinicopathological parameters, tumor stroma, and extent of LVI were assessed (focal: <5 spaces, extensive: ≥5 spaces). PFS and OS were evaluated using Kaplan-Meier methodology. Univariable and multivariable Cox proportional hazards models were created to determine prognostic survival-related risk factors. RESULTS: A total of 670 tumor samples were included in the analysis. Median age at diagnosis was 47 years (IQR: 38-60), 457 patients (72%) had a 2018 International Federation of Gynecology and Obstetrics (FIGO) stage I tumor, and 155 tumors (28%) were flat and/or ulcerated. There were 303 nonkeratinizing tumors (51%), 237 keratinizing tumors (40%), and 356 histologic grade 2 tumors (61%). Quantifiable LVI was present in 321 cases (51%; 23% focal and 33% extensive). On multivariable analysis for PFS, extensive and focal LVI had worse outcomes compared to negative LVI (HR: 2.38 [95% CI: 1.26-4.47] and HR: 1.54 [95% CI: 0.76-3.11], respectively; P = 0.02). The difference did not reach statistical significance for OS. CONCLUSION: Presence of LVI is a prognostic marker for patients with cervical SCC. Quantification (extensive vs. focal vs. negative) of LVI may be an important biomarker for oncologic outcome.
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Carcinoma de Células Escamosas , Neoplasias do Colo do Útero , Feminino , Humanos , Adulto , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Estadiamento de Neoplasias , Colo do Útero/patologia , Metástase Linfática , Carcinoma de Células Escamosas/cirurgia , Carcinoma de Células Escamosas/patologia , Neoplasias do Colo do Útero/cirurgia , Neoplasias do Colo do Útero/patologia , Invasividade Neoplásica/patologiaRESUMO
â¢Cervical PEComas are rare neoplasms which present a diagnostic challenge.â¢Large tumour size is an important clinical prognosticator in cervical PEComa.â¢All reported cases of cervical PEComa classified as benign by Folpe criteria behaved in benign fashion clinically.â¢Tumours ≤ 4 cm may be assessed with cone biopsy, and simple hysterectomy considered if no adverse pathologic features.â¢Molecular characterization and linkage with coordinated rare tumour registries may identify novel treatments.
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It is well recognized that some patients with endometrioid gynecological cancers have tumors arising in multiple sites (ovary, endometrium, and endometriosis) at the time of diagnosis. Molecular analysis has helped discern whether these multisite cancers represent synchronous primary tumors or alternatively metastatic disease. We present a complex case of a patient with endometrioid carcinomas arising in multiple sites. We discuss the use of mutation profiling to discern clonality and highlight how this information may inform the clinical management of such cases.
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Silva invasion pattern can help predict lymph node metastasis risk in endocervical adenocarcinoma. We analysed Silva pattern of invasion and lymphovascular invasion to determine associations with clinical outcomes in stage IA and IB1 endocervical adenocarcinomas. International Federation of Gynecology and Obstetrics (FIGO; 2019 classification) stage IA-IB1 endocervical adenocarcinomas from 15 international institutions were examined for Silva pattern, presence of lymphovascular invasion, and other prognostic parameters. Lymph node metastasis status, local/distant recurrences, and survival data were compared using appropriate statistical tests. Of 399 tumours, 152 (38.1%) were stage IA [IA1, 77 (19.3%); IA2, 75 (18.8%)] and 247 (61.9%) were stage IB1. On multivariate analysis, lymphovascular invasion (p=0.008) and Silva pattern (p<0.001) were significant factors when comparing stage IA versus IB1 endocervical adenocarcinomas. Overall survival was significantly associated with lymph node metastasis (p=0.028); recurrence-free survival was significantly associated with lymphovascular invasion (p=0.002) and stage (1B1 versus 1A) (p=0.002). Five and 10 year overall survival and recurrence-free survival rates were similar among Silva pattern A cases and Silva pattern B cases without lymphovascular invasion (p=0.165 and p=0.171, respectively). Silva pattern and lymphovascular invasion are important prognostic factors in stage IA1-IB1 endocervical adenocarcinomas and can supplement 2019 International Federation of Gynecology and Obstetrics staging. Our binary Silva classification system groups patients into low risk (patterns A and B without lymphovascular invasion) and high risk (pattern B with lymphovascular invasion and pattern C) categories.
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Adenocarcinoma , Carcinoma , Neoplasias do Colo do Útero , Adenocarcinoma/patologia , Carcinoma/patologia , Feminino , Humanos , Metástase Linfática , Estadiamento de Neoplasias , Prognóstico , Estudos RetrospectivosRESUMO
OBJECTIVES: The aims of this article were to describe 2 patients with a pathological diagnosis of differentiated exophytic vulvar intraepithelial lesion and to summarize the literature regarding this relatively new diagnosis. MATERIALS AND METHODS: The existing literature was searched on December 1, 2021, using the MEDLINE database (1966-2021), and all combinations of the following search terms were used: "differentiated exophytic vulvar intraepithelial lesion" and "differentiated vulvar intraepithelial neoplasia." RESULTS: Patients were postmenopausal and reported persistent vulvar itch associated with white hypertrophic plaques. Initial biopsies did not identify differentiated exophytic vulvar intraepithelial lesion. Invasive squamous cell carcinoma was found in both cases after surgical excision. CONCLUSIONS: Differentiated vulvar intraepithelial lesions and invasive squamous cell carcinoma should be considered in the differential diagnosis of vulvar itch associated with hypertrophic plaques in postmenopausal women. Excision of suspicious plaques is recommended for definitive diagnosis.
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Carcinoma in Situ , Carcinoma de Células Escamosas , Doenças da Vulva , Neoplasias Vulvares , Carcinoma in Situ/diagnóstico , Carcinoma in Situ/patologia , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/patologia , Feminino , Humanos , Vulva/patologia , Doenças da Vulva/diagnóstico , Doenças da Vulva/patologia , Doenças da Vulva/cirurgia , Neoplasias Vulvares/diagnóstico , Neoplasias Vulvares/patologia , Neoplasias Vulvares/cirurgiaRESUMO
PURPOSE: The 2018 International Federation of Gynecology and Obstetrics (FIGO) update on cervical cancer staging eliminated horizontal tumor extent (HZTE) as a staging parameter in stage IA (microscopic) disease. We aimed to determine whether HZTE correlates with outcomes in early stage ECAs and FIGO should reinstate HZTE as a staging parameter in futures updates. METHODS: We retrospectively analyzed 416 FIGO 2009 stage I ECAs from 17 institutions and re-assigned stage using FIGO 2018. Correlation between HZTE, overall (OS) and recurrence free survival (RFS) was performed using univariable and multivariable analyses. RESULTS: Re-staging 416 cases resulted in 126 (30.3%) IA and 290 (69.7%) IB cases; 85 (67.5%) IA tumors had HZTE ≤ 7 mm, while 41 (32.5%) were > 7 mm; 32 (11%) IB tumors had HZTE ≤ 7 mm, while 258 (89%) were > 7 mm (p = 0.0001). Four (3.2%) IA (1 IA1, 3 IA2) patients developed recurrence (3 ≤ 7 mm, 1 > 7 mm) compared to 41 (14.1%) IB patients (p = 0.002). Fourteen IB and no IA patients died of disease (8 IB1, 1 ≤ 7 mm). Cox univariate analysis demonstrated that only RFS is significantly influenced by HZTE (p = 0.01), while OS and RFS were not influenced by HZTE on multivariate analysis. CONCLUSION: HZTE has limited prognostic value in early stage ECAs and is only associated with RFS on univariate but not multivariate analysis. HZTE does not improve prognostication of patients with stage I ECAs as per 2018 FIGO staging. Consequently, the rationale to remove this variable from FIGO staging is justified for ECAs.
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Adenocarcinoma/patologia , Histerectomia/métodos , Neoplasias do Colo do Útero/patologia , Adenocarcinoma/cirurgia , Adulto , Idoso , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Neoplasias do Colo do Útero/cirurgiaRESUMO
HIK1083 and trefoil factor 2 (TFF2) are known to be expressed in gastric-type carcinoma (GAS), but they do not reliably mark all GASs, and focal expression can be missed in biopsy specimens. We aimed to investigate whether claudin-18 and alpha-methylacyl-CoA racemase (AMACR) could be surrogate markers to separate GAS from other types of endocervical adenocarcinoma (ECA) and to compare their usefulness with that of HIK1083 and TFF2. Claudin-18 and AMACR immunohistochemistry was performed, and the results were compared with that of TFF2 and HIK1083, using whole sections of 75 ECAs (22 GASs and 53 non-GASs) and 179 ECAs with tissue microarrays (TMAs). TMAs were built to simulate the assessment of immunohistochemical stains in small biopsies. Any membranous (claudin-18) or cytoplasmic/membranous (AMACR, TFF2, HIK1083) staining of >5% of tumor cells was considered positive. Of 75 ECAs with whole sections, claudin-18 was significantly more frequently expressed in GASs (21/22) compared with non-GASs (8/53) (P<0.01). In ECAs with TMAs, claudin-18 expression was significantly frequent in GASs (15/23, 65.2%) than in non-GASs (3/152, 2.0%; all usual-type) (P<0.01). All claudin-18-positive GASs showed intense staining except 1 case. Claudin-18 shared the same degree of sensitivity and specificity with HIK1083 and TFF2. Three clear cell carcinomas were positive for claudin-18, but none showed intense staining. AMACR was expressed in a subset of ECAs and showed no impact in distinguishing between GAS and other ECAs. Our results suggest that claudin-18 is a promising surrogate marker to separate GAS from other types of ECA, including clear cell carcinoma.
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Adenocarcinoma , Carcinoma , Claudinas/metabolismo , Neoplasias Gástricas , Neoplasias do Colo do Útero , Adenocarcinoma/patologia , Biomarcadores Tumorais , Carcinoma/patologia , Feminino , Humanos , Racemases e Epimerases , Neoplasias do Colo do Útero/patologiaRESUMO
Next-generation sequencing assays are capable of identifying cancer patients eligible for targeted therapies and can also detect germline variants associated with increased cancer susceptibility. However, these capabilities have yet to be routinely harmonized in a single assay because of challenges with accurately identifying germline variants from tumor-only data. We have developed the Oncology and Hereditary Cancer Program targeted capture panel, which uses tumor tissue to simultaneously screen for both clinically actionable solid tumor variants and germline variants across 45 genes. Validation using 14 tumor specimens, composed of patient samples and cell lines analyzed in triplicate, demonstrated high coverage with sensitive and specific identification of single-nucleotide variants and small insertions and deletions. Average coverage across all targets remained >2000× in 198 additional patient tumor samples. Analysis of 55 formalin-fixed, paraffin-embedded tumor samples for the detection of known germline variants within a subset of cancer-predisposition genes, including one multiexon deletion, yielded a 100% detection rate, demonstrating that germline variants can be reliably detected in tumor samples using a single panel. Combining targetable somatic and actionable germline variants into a single tumor tissue assay represents a streamlined approach that can inform treatment for patients with advanced cancers as well as identify those with potential germline variants who are eligible for confirmatory testing, but would not otherwise have been identified.
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Predisposição Genética para Doença/genética , Células Germinativas , Mutação em Linhagem Germinativa , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Neoplasias/diagnóstico , Neoplasias/genética , Alelos , Estudos de Coortes , Variações do Número de Cópias de DNA , Confiabilidade dos Dados , Feminino , Testes Genéticos/métodos , Humanos , Mutação INDEL , Polimorfismo de Nucleotídeo Único , Prognóstico , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
Uterine sarcomas represent a clinical challenge because of their difficult diagnosis and the poor prognosis of certain subtypes. The aim of this study was to evaluate the expression of the special AT-rich sequence-binding protein 2 (SATB2) in endometrial stromal sarcoma (ESS) and other types of uterine sarcoma by immunohistochemistry. We studied the expression of SATB2 on 71 full tissue sections of endometrial stromal nodule, low-grade ESS, uterine leiomyomas and leiomyosarcoma, undifferentiated uterine sarcoma, adenosarcoma, and carcinosarcoma samples. Nuclear SATB2 expression was then evaluated in an extended sample set using a tissue microarray, including 78 additional uterine tumor samples. Overall, with a cut-off of ≥10% of tumor cell staining as positive, the nuclear SATB2 score was negative in all endometrial stromal nodule samples (n=10) and positive in 83% of low-grade ESS samples (n=29/35), 40% of undifferentiated uterine sarcoma (n=4/10), 13% of leiomyosarcoma (n=2/16), 14% of adenosarcoma (n=3/22), and 8% carcinosarcoma (n=2/25) samples. Furthermore, in ESS patients, direct comparison of nuclear SATB2 scores with clinicopathologic parameters and other reported biomarkers such as progesterone receptor and estrogen receptor showed that nuclear SATB2 was associated with PR expression and a decreased risk of disease-specific death (odds ratio=0.06, 95% confidence interval=0.04-0.81, P=0.04). Our data suggest that SATB2 could be a marker with relative sensitivity (83%) for distinguishing between endometrial stromal nodule and ESS with potential prognostic value.
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Adenossarcoma/patologia , Carcinossarcoma/patologia , Leiomioma/patologia , Leiomiossarcoma/patologia , Proteínas de Ligação à Região de Interação com a Matriz/metabolismo , Sarcoma do Estroma Endometrial/patologia , Fatores de Transcrição/metabolismo , Neoplasias Uterinas/patologia , Adenossarcoma/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinossarcoma/genética , Estudos de Coortes , Feminino , Humanos , Leiomioma/genética , Leiomiossarcoma/genética , Proteínas de Ligação à Região de Interação com a Matriz/genética , Pessoa de Meia-Idade , Estudos Retrospectivos , Sarcoma do Estroma Endometrial/genética , Fatores de Transcrição/genética , Neoplasias Uterinas/genética , Adulto JovemRESUMO
Gastric-type carcinoma (GAS) is the most common human papilloma virus-independent endocervical adenocarcinoma (ECA), characterized by an aggressive behavior. Trefoil factor 2 (TFF2) is a mucin-associated peptide expressed in normal gastric but not endocervical glands. This study was carried out to investigate whether TFF2 could be a surrogate marker to separate GAS from other types of ECA. ECAs from 9 international institutions were reviewed for consensus histotype. Of them, expression of TFF2 was immunohistochemically examined compared with that of HIK1083, using whole sections of 50 ECAs (10 GASs and 40 non-GASs) and 179 ECAs (24 GASs and 155 non-GASs) with tissue microarrays (TMAs). TMAs were assessed to simulate assessment of immunohistochemical stains in small biopsies. Both markers were similarly scored, and any cytoplasmic/membranous staining of >5% of tumor cells was considered positive. Of 50 ECAs with whole sections, TFF2 was significantly more frequently expressed in GASs (8/10) compared with non-GASs (5/40) (P<0.01). In 179 ECAs with TMAs, TFF2 was also significantly more frequently expressed in GASs (7/24) compared with non-GASs (4/155) (P<0.01). There was no significant difference in specificity among the 2 markers. Double positivity for TFF2 and HIK1083 in ECAs was highly specific in separating GASs from non-GAS (P<0.01). A significantly smaller percentage of GASs were TFF2 positive in TMAs than in whole sections (P<0.01). Our results suggest that TFF2 is a promising marker, along with HIK1083, to confirm a diagnosis of GAS. This marker may be negative in small biopsies, indicating the necessity of using other exclusionary markers in combination with rigorous morphologic review and extensive sampling in resection specimens.
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Adenocarcinoma/diagnóstico , Carcinoma/diagnóstico , Neoplasias Gástricas/diagnóstico , Fator Trefoil-2/metabolismo , Neoplasias do Colo do Útero/diagnóstico , Adenocarcinoma/patologia , Biomarcadores/metabolismo , Carcinoma/patologia , Diagnóstico Diferencial , Feminino , Humanos , Imuno-Histoquímica , Neoplasias Gástricas/patologia , Análise Serial de Tecidos , Fator Trefoil-2/genética , Neoplasias do Colo do Útero/patologiaRESUMO
AIMS: Differentiated vulvar intraepithelial neoplasia (dVIN), the precursor lesion to human papillomavirus-independent vulvar squamous cell carcinoma (VSCC), can be difficult to distinguish from vulvar inflammatory dermatoses. Our goal was to determine if p53 could be a useful biomarker for dVIN, by characterizing p53 percentage, intensity and patterns of staining in dVIN and its histological mimics. METHODS AND RESULTS: We studied p53 immunohistochemical staining patterns in 16 dVIN cases and 46 vulvar non-neoplastic squamous lesions [12 lichen sclerosus (LS); seven lichen simplex chronicus; three lichen planus (LP); six psoriasis; 13 spongiotic dermatitis (SPO); and five candidiasis]. dVIN cases were adjacent to a p16-negative invasive VSCC in resection specimens. All dVIN cases showed null-type or moderate to strong uniform p53 staining in >70% of basal cells, with moderate to strong continuous parabasal staining extending to two-thirds of the epidermis. This was in contrast to weak or weak to moderate patchy p53 staining in the majority of other lesions. Moderate to strong and increased basal p53 staining (≥70%) was also observed in a subset of LS cases (5/12, 42%), LP cases (1/3, 33%), and SPO cases (36%, 4/11); however, in all categories, this was limited to the basal layer, and any staining in the parabasal layers was patchy. CONCLUSION: Strong and uniform p53 staining of basal cells, extending into the parabasal layers, and a complete absence of staining (null type) is useful in distinguishing dVIN from other mimics in the vulva. p53 staining of lesser intensity or quantity, particularly basal overexpression only, overlaps with that in vulvar inflammatory lesions.
Assuntos
Carcinoma in Situ/diagnóstico , Imuno-Histoquímica/métodos , Proteína Supressora de Tumor p53/análise , Neoplasias Vulvares/diagnóstico , Biomarcadores Tumorais/análise , Candidíase/diagnóstico , Candidíase/patologia , Carcinoma in Situ/patologia , Dermatite/diagnóstico , Dermatite/patologia , Diagnóstico Diferencial , Técnicas e Procedimentos Diagnósticos , Feminino , Humanos , Líquen Escleroso e Atrófico/diagnóstico , Líquen Escleroso e Atrófico/patologia , Neurodermatite/diagnóstico , Neurodermatite/patologia , Psoríase/diagnóstico , Psoríase/patologia , Sensibilidade e Especificidade , Dermatopatias/diagnóstico , Dermatopatias/patologia , Vulva/patologia , Neoplasias Vulvares/patologiaRESUMO
OBJECTIVE: Prognostic factors for endocervical adernocarcinomas are well known, but little is known about prognostic biomarkers influencing outcome for the newly defined International Federation of Gynecology and Obstetrics (FIGO) 2018 IB sub-stages. The aim of this study was to identify prognostic biomarkers influencing recurrence-free and overall survival for FIGO 2018 stage IB cervical adenocarcinoma sub-types. We sought to identify these factors using a large international multi-institutional series of cases. METHODS: Stage IB endocervical adenocarcinomas were retrospectively collected from nine international institutions; full slide sets (n=464) were used to assign prognostic biomarkers. Inclusion criteria were the following: FIGO stage IB endocervical adenocarcinomas with follow-up in which all paraffin blocks/glass slides were available for review and/or additional studies and the patient was surgically treated from 1985 to 2019. The types of specimens included in the study were conizations, trachelectomies, and simple/radical hysterectomies with or without lymph node samples. We excluded in situ carcinomas, squamous cell carcinomas, adenosquamous carcinomas, tumors with a neuroendocrine component, carcinosarcomas, and any tumor showing clinical, macroscopic, or microscopic features suggesting a lower uterine segment, uterine corpus, or an adnexal primary origin. Tumors treated with neoadjuvant chemotherapy and/or radiation therapy were also excluded, as well as biopsies and loop electrosurgical excision procedures. RESULTS: Of 464 cases, 225 (48%) were stage IB1, 177 (38%) were stage IB2, and 62 (13%) were stage IB3. Five-year and 10-year recurrence-free survivals were statistically different among stage IB sub-types (p=0.005). Silva pattern of invasion was significant for recurrence-free survival at 5 and 10 years (p=0.04); overall survival and recurrence-free survival were higher in human papillomavirus (HPV)-associated cases (p=0.007 and p=0.001, respectively) and in cases without lymphovascular invasion (p=0.004 and p=0.00001, respectively). Factors that significantly influenced recurrence-free survival were HPV-independent status (p=0.05; HR 2.31; 95% CI 1.02 to 5.46), presence of lymphovascular invasion (p=0.011; HR 3.50; 95% CI 1.33 to 9.19), and presence of lymph node metastasis (p=0.016; HR 2.66; 95% CI 1.20 to 5.90). CONCLUSION: HPV status and the presence of lymphovascular invasion are prognosticators in stage IB endocervical adenocarcinoma sub-types. These parameters should be included in future sub-staging modifications of FIGO stage IB endocervical adenocarcinomas and in treatment strategies.