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Immunohistochemical Loss of DPC4 in Tumors With Mucinous Differentiation Arising in or Involving the Gynecologic Tract
Kwon, Dong Hyang M.D.; Malpica, Anais M.D.; Zaleski, Michael M.D.; Euscher, Elizabeth D. M.D.; Ramalingam, Preetha M.D.
doi : 10.1097/PGP.0000000000000754
November 2021 - Volume 40 - Issue 6 - p 523-532
DPC4 immunohistochemistry (IHC) is usually part of the work-up of mucinous neoplasms in the ovary where the distinction between an ovarian primary and metastatic pancreaticobiliary adenocarcinoma (PanACa) must be made. Although DPC4 IHC is lost in about 55% (46%–61%) of PanACas and typically retained in most primary ovarian mucinous neoplasms, no study has evaluated the expression of this marker in a large cohort of neoplasms arising in or involving gynecologic (GYN) organs. In this study, we retrospectively analyzed the expression of DPC4 IHC in a total of 251 tumors and lesions related to the GYN tract in which DPC4 IHC stain was performed during the initial pathology evaluation. Of these, 138 were primary GYN tumors and lesions, 31 were metastatic GYN tumors involving non-GYN sites, and 83 were metastatic non-GYN tumors involving the GYN tract. We identified 27 cases with loss of DPC4 IHC expression of which 20 cases met the inclusion criteria (i.e. clinical information was available to determine the site of tumor origin). We observed that loss of DPC4 nuclear expression was most commonly seen in tumors of endocervical origin (n=7), of which 5 were gastric-type cervical adenocarcinomas (GCxACa) and 2 were usual-type cervical adenocarcinomas, either primary or metastatic. This was followed by tumors of the pancreaticobiliary tract (n=5), ovary (n=2), and appendix (n=1). In addition, 1 gastric-type vaginal adenocarcinoma (GVaACa) also showed loss of DPC4. Our findings indicate that in female patients with mucinous neoplasms involving the ovary or other sites, with loss of DPC4 by IHC, and negative pancreaticobiliary imaging, the possibility of an occult GCx/GVaACa, and rarely an ovarian primary must be considered.
International Endocervical Adenocarcinoma Criteria and Classification (IECC): An Independent Cohort With Clinical and Molecular Findings
Ren, Hezhen M.D.; Almadani, Noorah M.D.; Pors, Jennifer M.D.; Leung, Samuel M.Sc.; Ho, Julie M.H.A.; Chow, Christine B.M.L.Sc.; Ta, Monica B.M.L.Sc.; Park, Kay J. M.D.; Stolnicu, Simona M.D. Ph.D.; Soslow, Robert M.D.; Huntsman, David M.D.; Gilks, Blake C. M.D.; Hoang, Lynn M.D.
doi : 10.1097/PGP.0000000000000764
November 2021 - Volume 40 - Issue 6 - p 533-540
Recently, the International Endocervical Adenocarcinoma Criteria and Classification (IECC) has reorganized the classification of endocervical adenocarcinomas (ECAs), separating them into human papilloma virus (HPV)-associated (HPVA) and HPVA independent (HPVI) categories. In this study, we sought to revalidate the IECC clinical findings in an independent cohort and assess the mutational differences between HPVA and HPVI ECAs using next generation sequencing. Consecutive cases of ECAs were reclassified under the IECC. Clinicopathologic information was collected and tissue was sent for targeted next-generation sequencing in 33 genes. Associations between HPV status, clinicopathologic parameters and mutation status, with survival were evaluated. The series comprised of 85/100 HPVA (63 HPVA-usual type, 4 villoglandular, 3 mucinous intestinal, 15 mucinous not otherwise specified) and 15/100 HPVI (9 gastric, 4 mesonephric, 1 clear cell, 1 not otherwise specified). HPVA ECAs presented at a lower age (P=0.001), smaller tumor sizes (P=0.011), less margin positivity (P=0.027), less Silva pattern C (P=0.002), and lower FIGO stages (P=0.020). HPVA had superior survival compared with HPVI ECA [overall survival (P=0.0026), disease-specific survival (P=0.0092), and progression-free survival (P=0.0041)]. Factors that correlated with worse prognosis irrespective of HPV status were FIGO stage, positive margins and lymphovascular invasion (P<0.05). TP53 mutations were detected in a significantly higher proportion of HPVIs than HPVAs (P<<0.001). The study revalidates the IECC system by reaffirming the clinical and prognostic differences between HPVA and HPVI ECAs in an independent dataset.
Pelvic and Ovarian Recurrence of Small HPV-associated Cervical Adenocarcinoma With Transformation to Neuroendocrine Carcinoma
Abu-Sinn, Duaa F.R.C.Path.; Jamison, Jackie F.I.B.M.S.; Evans, Matthew F.R.C.Path.; McCluggage, W. Glenn F.R.C.Path.
doi : 10.1097/PGP.0000000000000749
November 2021 - Volume 40 - Issue 6 - p 541-548
The phenomenon of small human papillomavirus–associated cervical adenocarcinomas involving the ovary via a transuterine and transtubal route is uncommon but well described in the literature. We report a unique case of a small human papillomavirus–associated cervical adenocarcinoma spreading to both ovaries and the pelvis via this route 22?mo after loop excision and trachelectomy and developing into a high-grade neuroendocrine carcinoma in the metastasis.
Digital Quantification of Ki-67 and PHH3 in the Classification of Uterine Smooth Muscle Tumors
Cao, Connie D. M.D.; Rico-Castillo, Jesus M.D.; De Cotiis, Dan M.D., Ph.D.; Richard, Scott D. M.D.; Rosenblum, Norman G. M.D., Ph.D.; Chan, Joanna S.Y. M.D.
doi : 10.1097/PGP.0000000000000739
November 2021 - Volume 40 - Issue 6 - p 549-555
Uterine smooth muscle tumors are the most common tumors of the female genital tract and include leiomyoma (LM) and its variants, smooth muscle tumors of uncertain malignant potential (STUMP), and leiomyosarcoma (LMS). Accurate diagnosis of LMS is determined by nuclear atypia, mitotic count, and the presence or absence of tumor cell necrosis, a process which is often difficult and subjective. In this study, we correlated digital quantification of proliferation marker Ki-67 and mitotic marker phosphohistone H3 (PHH3) to mitotic count, classification of uterine smooth muscle tumors, and clinical outcomes. A total of 39 cases (17 LMS, 5 STUMP, 10 LM with bizarre nuclei, and 7 LM) were included. Mitotic count, Ki-67, and PHH3 were significantly correlated. When comparing the LMS group to the STUMP, LM with bizarre nuclei, and LM groups combined, LMS showed a significantly greater digital quantification of Ki-67 (median 10.6% vs. 0.4%, P<0.001) and PHH3 (median 0.5% vs. 0.14%, P=0.022). Ki-67 was a better predictor of LMS compared with PHH3 (area under the curve 0.92 vs. 0.73, P=0.017). Above a threshold Ki-67 value of 3.8%, the sensitivity was 82% and specificity was 91%. Clinical outcomes were available for 10 patients (8 LMS and 2 STUMP), and inferior progression-free survival was noted for patients with higher Ki-67 values. Overall, this study suggests that digital quantification of Ki-67 can potentially aid in diagnosis of LMS.
The Diagnostic Criteria for Chronic Endometritis: A Survey of Pathologists
Margulies, Samantha L. M.D.; Dhingra, Isha M.D.; Flores, Valerie M.D.; Hecht, Jonathan L. M.D., Ph.D.; Fadare, Oluwole M.D.; Pal, Lubna M.B.B.S. F.R.C.O.G., M.S.; Parkash, Vinita M.B.B.S., M.P.H.
doi : 10.1097/PGP.0000000000000737
November 2021 - Volume 40 - Issue 6 - p 556-562
While acute endometritis is a reasonably well-defined entity of ascending infection and attendant active inflammation, chronic endometritis is less well defined. As part of a broad effort to define and refine the diagnostic criteria and management of the disease, we conducted a survey of pathologists to understand the variability in diagnostic criteria and implications of the diagnosis of nonspecific, nonobstetric chronic endometritis. Members of national and international professional pathology societies were surveyed utilizing anonymous electronic surveys designed to examine diagnostic criteria, etiological understanding and treatment implications of a pathologic diagnosis of nonspecific, nonobstetric chronic endometritis. There was substantial variability among pathologists in the diagnostic criteria used for making a diagnosis of nonspecific, nonobstetric chronic endometritis, with 28.5% of pathologists using the presence of a single plasma cell for making the diagnosis. There was additional variability in the use of special stains, reporting in the presence of coexisting lesions and the hormonal stage of the endometrium. There were no differences between generalists and specialists in the diagnostic criteria used, except the significantly greater likelihood of specialists making the diagnosis in gestational endometrium. The substantial variability in diagnostic criteria for nonspecific, nonobstetric chronic endometritis among pathologists, including among gynecologic pathologists, has the potential to confound the management of patients. Standardization of diagnostic criteria for chronic endometritis is essential to understand the implications of the diagnosis.
PD-L1 and Mismatch Repair Status in Uterine Carcinosarcomas
Jenkins, Taylor M. M.D.; Cantrell, Leigh A. M.D.; Stoler, Mark H. M.D.; Mills, Anne M. M.D.
doi : 10.1097/PGP.0000000000000752
November 2021 - Volume 40 - Issue 6 - p 563-574
Uterine carcinosarcomas have few adjuvant treatment options. Programmed cell death ligand-1 (PD-L1) expression in these tumors may predict response to checkpoint inhibitor therapies. An increase in PD-L1 expression has been shown in endometrial carcinomas with mismatch repair (MMR) deficiencies; however, few studies have evaluated PD-L1 expression in uterine carcinosarcomas. We examined PD-L1 expression in 41 cases of uterine carcinosarcoma using combined positive scores (CPS) and tumor proportion scores (TPS), and correlated with MMR status, p53 expression, and epithelial histotype. In addition to confirming the diagnosis of carcinosarcoma, the epithelial components were stratified based on endometrioid versus serous histology. Thirty-three cases (80%) were positive for PD-L1, defined as a CPS score of ?1 or a TPS score of ?1%. Twelve cases (29%) showed high expression of PD-L1, defined as a CPS score of ?10 or a TPS score of ?10%. The majority of the morphologically adjudicated carcinosarcomas had a serous epithelial component (83%) rather than endometrioid (17%), which was reinforced by aberrant p53 staining predominantly within cases with serous morphology. The majority of carcinosarcomas showed at least focal PD-L1 expression, predominantly in tumor-associated immune cells. Carcinosarcomas with endometrioid morphology were significantly more likely to have high-level PD-L1 (5/7 vs. 7/34; P=0.015). MMR-deficient carcinosarcomas were also more likely to have high-level PD-L1 (2/3 vs. 10/28); however, this did not reach statistical significance (P=0.2) and overall MMR-deficiency was uncommon (3 cases, 7%). These findings suggest that PD-L1 may be additive to MMR testing as a predictive biomarker for checkpoint inhibitor vulnerability in carcinosarcomas.
PD-L1 Expression in Mismatch Repair-deficient Endometrial Carcinoma and Tumor-associated Immune Cells: Differences Between MLH1 Methylated and Nonmethylated Subgroups
Kir, Gozde M.D.; Olgun, Zeynep C. M.D.; Soylemez, Tuce M.D.; Aydin, Abdullah M.D.; Demircan, Berna M.D.; Kaya, Ibrahim A. M.D.; McCluggage, W. Glenn F.R.C.Path
doi : 10.1097/PGP.0000000000000750
November 2021 - Volume 40 - Issue 6 - p 575-586
Mismatch repair (MMR)-deficient endometrial carcinomas show increased programmed cell death-ligand 1 (PD-L1) expression compared with MMR-intact endometrial carcinomas, but there are limited data regarding PD-L1 expression between sporadic and inherited carcinomas exhibiting MMR loss. Most of the studies investigating PD-L1 expression in endometrial carcinoma have used tissue microarrays and did not examine all tumor blocks. In this study, we analyzed the expression of PD-L1 in resection specimens of 176 consecutive endometrial carcinomas using all tumor blocks; we compared PD-L1 expression in MMR-deficient endometrial carcinomas, including the MLH1 and PMS2-loss subgroup, and the other MMR-loss subgroups (MSH2 and MSH6, isolated PMS2, and isolated MSH6), with the MMR-intact subgroup. MLH1 methylation was performed in tumors with MLH1 and PMS2 loss. Tumor cell (TC) and tumor-associated immune cell (IC) PD-L1 positivity with a 1% cutoff was observed in 21% (n=37) and 66.5% (n=117) of cases, respectively, and with a 5% cutoff in 5.1% (n=9) and 39.8% (n=70) of cases, respectively. MMR protein deficiency was a statistically significant parameter associated with IC PD-L1 positivity, with 1% and 5% cutoffs on multivariate analysis [odds ratio (OR)=5.236, 95% confidence interval (CI)=2.075-13.211, P=0.001, and OR=3.702, 95% CI=1.759-7.791, P=0.001, respectively]. The multivariate analysis showed that IC PD-L1 positivity, using both 1% and 5% cutoffs, was significantly associated with the MLH1 and PMS2 loss compared with the MMR protein-intact subgroup (MLH1 and PMS2 loss for 1% cutoff: OR=5.104, 95% CI=1.876–13.881, P=0.001, and for 5% cutoff: OR=3.322, 95% CI=1.540–7.166, P=0.002). Squamous differentiation was an independent predictor for TC PD-L1 positivity, with a 5% cutoff (OR=6.102, 95% CI=1.280–10.096, P=0.026). Larger tumor size was an independent predictive factor for IC PD-L1 positivity with a 1% cutoff (OR=6.757, 95% CI=1.569–29.109, P=0.010). Overall, 48 (92.3%) of 52 MLH1 methylated tumors showed IC PD-L1 positivity with 1% cutoff, and 34 (65.4%) of 52 MLH1 methylated tumors showed IC PD-L1 positivity with 5% cutoff. Our results show a higher rate of IC PD-L1 positivity than in previous studies. This is likely due in part to the use of all tumor blocks. MLH1 and PMS2 loss was an independent predictive factor for IC PD-L1 positivity, with both 1% and 5% cutoffs. Using univariate analysis, we observed decreased disease-free survival for IC PD-L1 positivity ?5%. Our study results should now be tested and proven in larger cohorts, with longer follow-up data.
Endometrial Adenocarcinomas With No Specific Molecular Profile: Morphologic Features and Molecular Alterations of “Copy-number Low” Tumors
Meljen, Vivienne T. M.D.; Mittenzwei, Rhonda M.D.; Wong, Janice M.S.; Puechl, Allison M.D.; Whitaker, Regina B.S.; Broadwater, Gloria M.S.; Hall, Allison H. M.D., Ph.D.; Bean, Sarah M. M.D.; Bentley, Rex C. M.D.; Elvin, Julia A. M.D.; Berchuck, Andrew M.D.; Previs, Rebecca A. M.D.; Strickland, Kyle C. M.D., Ph.D.
doi : 10.1097/PGP.0000000000000747
November 2021 - Volume 40 - Issue 6 - p 587-596
The study evaluated morphologic patterns, mutational profiles, and ?-catenin immunohistochemistry (IHC) in copy-number low (CNL) endometrial adenocarcinomas (EAs). CNL EAs (n=19) with next-generation or whole genome sequencing results and available tissue for IHC were identified from our institutional database. Clinical data and histologic slides were reviewed. IHC for ?-catenin was performed and correlated with mutation status. Images of digital slides of CNL EAs from The Cancer Genome Atlas (TCGA) database (n=90) were blindly reviewed by 4 pathologists, and morphology was correlated with mutation status. Categorical variables were analyzed using the Fisher exact test, and agreement was assessed using Fleiss ?. CTNNB1 mutations were present in 63% (12/19) of CNL EAs. ?-catenin nuclear localization was present in 83% of CTNNB1-mutated tumors (10/12) and in 0% (0/7) of CTNNB1-wildtype tumors (sensitivity 0.83, specificity 1.00). Squamous differentiation (SD) was present in 47% (9/19) and was more often observed in CTNNB1-mutated tumors (P=0.02). Mucinous differentiation (MD) was associated with KRAS mutations (P<0.01). Digital image review of TCGA CNL EAs revealed that pathologist agreement on SD was strong (?=0.82), whereas agreement on MD was weak (?=0.48). Pathologists identified SD in 22% (20/90), which was significantly associated with the presence of CTNNB1 mutations (P<0.01). CNL EAs demonstrate several morphologies with divergent molecular profiles. SD was significantly associated with CTNNB1 mutations and nuclear localization of ?-catenin in these tumors. Nuclear expression of ?-catenin is a sensitive and specific IHC marker for CTNNB1 mutations in CNL EAs. CNL EAs with KRAS mutations often displayed MD.
Vascular Pseudoinvasion After Endometrial Ablation
Karpathiou, Georgia M.D., B.Sc., Ph.D.; Corsini, Thomas M.D.; Dagher, Sami M.D.; Chauleur, Celine M.D., Ph.D.; Peoc’h, Michel M.D., Ph.D.
doi : 10.1097/PGP.0000000000000748
November 2021 - Volume 40 - Issue 6 - p 597-601
Vascular pseudoinvasion or displacement of tumor or normal endometrial tissue is a potential pitfall in uterine pathology. The proposed mechanisms of this phenomenon are mostly associated with the uterine manipulator used during minimally invasive hysterectomies. The aim of this report is to describe vascular pseudoinvasion in a still unreported setting, that of a postendometrial ablation hysterectomy, and to provide a summary of studies dealing with artifactual or nonmalignant myometrial vessel involvement by normal or neoplastic endometrial tissue.
A Clinical and Pathologic Exploration of Suspected Peritoneal Endometriotic Lesions
Watkins, Jaclyn C. M.D., M.S.; DiVasta, Amy D. M.D., M.M.Sc.; Vitonis, Allison F. M.S.; Crum, Christopher P. M.D.; Laufer, Marc R. M.D.; Terry, Kathryn L. Sc.D.; Howitt, Brooke E. M.D.; Missmer, Stacey A. Sc.D.
doi : 10.1097/PGP.0000000000000743
November 2021 - Volume 40 - Issue 6 - p 602-610
Endometriosis is generally histopathologically defined as the presence of at least 2 of the following: endometrial stroma, Müllerian epithelium, and/or hemosiderin-laden macrophages (HLM). Despite clinically evident endometriotic lesions, biopsies are frequently nondiagnostic. In this study, we conducted a large-scale review of biopsies of lesions clinically thought to represent endometriosis and correlate the histologic findings with clinical appearance to expand sensitivity of the pathologic definition of endometriosis, particularly in patients on hormonal therapy. In all, 112 biopsies from 78 patients (mean age=25, range 18–39?yr) were reviewed for histopathologic features suggestive of or diagnostic for endometriosis including the presence of endometrial stroma, Müllerian epithelium, dystrophic calcifications, HLM, chronic inflammation, adhesions, and vascular proliferation. Endometriosis was confirmed by pathologic criteria in 37 of 78 patients (47%). Biopsies from patients on hormonal therapy (n=62, 80%) were significantly less likely to meet pathologic criteria for endometriosis (P=0.01). Nondiagnostic biopsies (70/112; 63%) frequently displayed HLM (20%), chronic inflammation (29%), dystrophic calcifications (26%), vascular proliferation (20%), or adhesions (20%) and were significantly more likely to have a vascular clinical appearance (P=0.01). Diagnostic biopsies (42/112; 38%) were more likely to have a blue/black clinical appearance (P=0.03), demonstrate HLM (P=0.004), and display pseudodecidualization (P=0.05). Patients with a high clinical suspicion of endometriosis have a range of histologic findings, with less than half meeting the current histopathologic criteria for diagnosing endometriosis. Given the heterogeneous histopathologic appearance, revision of the histologic criteria may be warranted with further exploration, particularly for lesions with predominantly vascular features.
FOXA1 Expression by Immunohistochemistry in Carcinosarcomas of the Endometrium and Ovary/Fallopian Tube
Karpathiou, Georgia M.D., B.Sc., Ph.D.; Chauleur, Celine M.D., Ph.D.; Dal Col, Pierre M.D.; Peoc’h, Michel M.D., Ph.D.
doi : 10.1097/PGP.0000000000000772
November 2021 - Volume 40 - Issue 6 - p 611-616
FOXA1, a transcription factor essential for the binding of other transcription factors on chromatin, is associated with hormone receptor-associated cancers, such as breast and endometrial cancer. It is also considered an antagonist of epithelial-to-mesenchymal transition (EMT). In endometrial cancer, FOXA1 is considered a tumor suppressor; in carcinosarcoma, one of the most aggressive and rare subtypes of endometrial cancer, thought to be derived through an EMT mechanism, FOXA1 has not been studied. Thus, the aim of this study was to investigate the possible expression of FOXA1 in carcinosarcomas, and its correlation with clinicopathologic factors. This was a retrospective study of 31 patients diagnosed with carcinosarcomas of the uterus or the adnexa. Histologic and clinical factors were correlated with the immunohistochemical expression of FOXA1. FOXA1 was expressed by 38.7% of the carcinomatous components and 16.1% of the sarcomatous components. FOXA1-positive sarcomatous components were seen only with positive carcinomatous components (P=0.004). FOXA1 expression was not associated with age, primary tumor site, stage, metastases, overall survival, or tumor relapse. FOXA1 expression in the carcinomatous component was associated with an absence of lymphovascular invasion or the presence of heterologous components. FOXA1 expression in the sarcomatous component was associated with rhabdomyosarcoma, rather than the chondrosarcoma heterologous component. Carcinosarcomas harbor FOXA1 expression, although it is in their carcinomatous rather than sarcomatous components, suggesting a possible role of FOXA1 in the EMT of carcinosarcomas. FOXA1 shows no prognostic significance in this tumor group.
Krukenberg Tumor of Ovary During Pregnancy: Learning From A Mistake
Jha, Shilpy M.D.; Mitra, Suvradeep M.D., D.M. (Histopathology); Patra, Susama M.D.; Sethi, Pruthwiraj M.S.; Jena, Saubhagya K. M.S.
doi : 10.1097/PGP.0000000000000733
November 2021 - Volume 40 - Issue 6 - p 617-620
Sertoli-Leydig cell tumor of the ovary with heterologous differentiation is a relatively uncommon tumor that occurs in females of variable age range. Krukenberg tumor (KT) is a relatively more common tumor of the ovary although only a few cases of KT occur during pregnancy making it an equally uncommon tumor in this setting. We received a unilateral ovarian mass in a 25-yr-old primigravida which we reported as Sertoli-Leydig cell tumor with heterologous (intestinal) differentiation based on its clinical and histomorphologic features. However, on further investigation, a gastric mass was found which was a signet-ring cell adenocarcinoma. We rectified our diagnosis of ovarian mass as KT. We retrospectively analyzed the reasons for our mistake and concluded that the rarity coupled with the nonclassic clinical features and histomorphology of KT during pregnancy pose challenges to the correct diagnosis. This report highlights the diagnostic challenges faced by us along with the ways to circumvent them in the future.
