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Integrated analysis of ovarian juvenile granulosa cell tumors reveals distinct epigenetic signatures and recurrent TERT rearrangements

Vougiouklakis, Theodore; Zhu, Kelsey; Vasudevaraja, Varshini; Serrano, Jonathan; Shen, Guomiao; Linn, Rebecca L; Feng, Xiaojun; Chiang, Sarah; Barroeta, Julieta E; Thomas, Kristen M; Schwartz, Lauren E; Shukla, Pratibha S; Malpica, Anais; Oliva, Esther; Cotzia, Paolo; DeLair, Deborah F; Snuderl, Matija; Jour, George
PURPOSE/OBJECTIVE:-truncating mutations. Conversely, the molecular underpinnings of the rare juvenile granulosa cell tumor (JGCT) have not been well elucidated. To this end, we applied a tumor-only integrated approach to investigate the genomic, transcriptomic, and epigenomic landscape of 31 JGCTs to identify putative oncogenic drivers. EXPERIMENTAL DESIGN/METHODS:Multipronged analyses of 31 JGCTs were performed utilizing a clinically validated next-generation sequencing (NGS)-panel targeting 580 cancer-related genes for genomic interrogation, in addition to targeted RNA NGS for transcriptomic exploration. Genome-wide DNA methylation profiling was conducted using an Infinium Methylation EPIC array targeting 866,562 CpG methylation sites. RESULTS:non-rearranged JGCTs under direct promoter control. Genome-wide DNA methylation rendered a clear delineation between AGCTs and JGCTs at the epigenomic level further supporting its diagnostic utility in distinguishing among these tumors. CONCLUSIONS:rearrangements in a subset of tumors. Our findings further offer insights into possible targeted therapies in a rare entity.
PMID: 35031544
ISSN: 1557-3265
CID: 5119182

Intratumoral budding is associated with poor clinical outcome in early-stage clear cell carcinoma of ovary

Lin, Lawrence Hsu; Zamuco, Ronaldo DeLeon; Shukla, Pratibha Sharma
AIMS/OBJECTIVE:Clear cell carcinoma of ovary (CCC) is considered a high-grade malignancy by default and the role of histological grading for assessing clinical outcome is not established. We aimed to evaluate histopathological features associated with clinical outcome in CCC patients. METHODS AND RESULTS/RESULTS:Seventy-six cases of CCC with available clinical follow-up information were studied. Histopathological features, including tumour size, architectural patterns, nuclear atypia, mitotic activity, intratumoral and peritumoral inflammation, presence of endometriosis, peritumoral and intratumoral budding, were evaluated. Multivariate analysis was performed with logistic regression and Kaplan-Meier survival curves with the log-rank test were used for survival analysis. Forty cases (53%) presented at stage I. Complete response to treatment was achieved in 65%, while 35% of patients had tumour recurrence or progression of disease despite treatment. At last follow-up, 13% had died of disease, 20% were alive with disease and 67% had no evidence of disease. Higher stage (P = 0.0016) and presence of intratumoral budding (P = 0.0454) were independently associated with recurrence/disease progression. Advanced stage (P = 0.0011), presence of lymph node involvement (P = 0.0003), intratumoral budding (P = 0.0023) and peritumoral budding (P = 0.0334) were significantly associated with shorter survival. Intratumoral budding was significantly associated with recurrent/progressive disease (P = 0.0195) and also shorter survival (P = 0.0277) within the cohort of low-stage (I/II) patients as well. CONCLUSION/CONCLUSIONS:We have shown that besides the classic prognostic factors of stage and lymph node status, the presence of tumour budding is associated with poorer outcome in patients with CCC. Specifically, evaluation of intratumoral budding may help to more clearly predict prognosis in patients with early-stage disease.
PMID: 34292622
ISSN: 1365-2559
CID: 5010652

Gynecologic Perivascular Epithelioid Cell Tumor (PEComa): Comparative Analysis of Proposed Algorithms for Prediction of Clinical Outcome

Shukla, Pratibha Sharma; Xia, Rong; Lin, Lawrence Hsu; Schwartz, Christopher J
Perivascular epithelioid cell tumors (PEComas) are rare mesenchymal tumors that co-express smooth muscle and melanocytic markers. They have a predilection for gynecologic organs where they present a unique diagnostic challenge due to morphologic and immunohistochemical overlap with more common smooth muscle and stromal tumors. Limited information regarding natural history owing to rarity of this tumor makes accurate risk stratification difficult. Five different prognostic classification systems (2 for PEComa of all sites and 3 specific for gynecologic PEComa) have been proposed. We have described clinicopathologic features of 13 new cases of gynecologic PEComa, and tested all 5 prognostic algorithms in a total of 67 cases of gynecologic PEComa (54 cases from previously published studies). Receiver Operating Characteristic curves were built and area under curve (AUC) was calculated to evaluate predictive accuracy. The 'modified gynecologic-specific criteria' showed high sensitivity and specificity and yielded the highest AUC (0.864). The earlier version of it, 'gynecology-specific criteria' suffered from lower specificity (AUC = 0.843). Post hoc McNemar test confirmed significant difference between the performances of 'modified gynecology-specific criteria' and 'gynecology-specific criteria' (p = .008). The 'original' Folpe criteria for PEComas of all sites showed low specificity, had lower AUC (0.591) and was inapplicable in 18% of cases. Its two later versions ('revised' Folpe criteria and 'modified' Folpe criteria) also yielded lower AUC (0.690 and 0.591respectively). We have shown that 'modified gynecologic-specific' algorithm predicts clinical outcome of gynecologic PEComa with high accuracy and have validated its use for prognostic stratification of gynecologic PEComa.
PMID: 34157139
ISSN: 1365-2559
CID: 4932022

Diseases of the Peritoneum

Chapter by: Shukla, Pratibha Sharma; Novo, Jorge E; Wei, Jian-Jun
in: Practical Gynecologic Pathology by Wei, Jian-Jun; Hui, Pei
[S.l.] : Springer, 2021
pp. 297-315
ISBN: 978-3-030-68607-9
CID: 4969062

Small tumor nests are associated with poor clinical outcome in clear cell carcinoma of ovary [Meeting Abstract]

Lin, L; Zamuco, R; Shukla, P
Background: Clear cell carcinoma of ovary (CCCO) accounts for 5-25% of ovarian carcinomas. Considered a high-grade malignancy by default, the role of histological grading for assessing clinical outcome is not established in CCCO. We aimed to evaluate histopathological features predictive of clinical outcome in patients with CCCO.
Design(s): Pathology database was searched after IRB approval. A total of 69 cases of CCCO were studied. Slides from primary tumor resection were reviewed blinded to outcome. The original diagnosis of CCCO was confirmed and the following histopathologic features were recorded: percentage of solid component, degree of nuclear atypia, mitotic activity, intratumoral inflammation, presence of small tumor nests (intratumoral single cells or clusters of <5 cells in non-hyalinized stroma, Figure 1A-B), tumor budding (peritumoral single cells or clusters of <5 cells), lymph node involvement and endometriosis. Information regarding age at diagnosis, clinical stage, treatment and followup was obtained from medical charts. Kaplan-Meier survival curves with log rank test, Fisher's exact test and Mann-Whitney test were used for statistical analysis.
Result(s): Median patient age was 52 years (range 26-75 years). Forty-nine (71%) tumors were associated with endometriosis and 37 (53%) presented at stage I. Ten (15%) patients died of disease, 14 (20%) were alive with active disease and 45 (65%) had no evidence of disease at last follow-up (median follow-up: 34.2 months, range 1.2 - 230.6). Advanced stage, positive lymph nodes and presence of small tumor nests were significantly associated with shorter overall survival (p=0.006, p<0.001, p=0.004, respectively; Figure 2A-C) and recurrence/progression despite treatment (p<0.0001, p=0.0011, p=0.0003, respectively; table 1). Also, within the cohort of low stage patients (stage I and II), presence of small tumor nests was associated with recurrence/disease progression (p=0.0014; table 1). None of the other studied features reached statistical significance for assessment of prognosis.
Conclusion(s): Besides the classic prognostic factors of stage and lymph node status, presence of small tumor nests seems to be associated with poorer outcome in patients with CCCO. Specifically, in patients with early stage disease, evaluation of small tumor nests may help to better determine prognosis. These findings should be further evaluated in larger studies
ISSN: 1530-0307
CID: 4857112

Prognostic impact of tumor microenvironment in carcinosarcoma of the female genital tract: A study of CD8+ tumor infiltrating lymphocytes and programmed death-ligand 1 (PD-L1) expression [Meeting Abstract]

Amezcua, J M G; Ordner, J; Shukla, P
Background: Carcinosarcoma (CS) of the female genital tract is an uncommon and highly aggressive malignancy which lacks effective therapeutic strategies and has poor prognosis. Tumor immune microenvironment (TME) profiles of various cancers based on PD-L1 expression and tumor-infiltrating lymphocytes (TILs) have been shown to affect prognosis. We aimed to investigate the prognostic significance of PD-L1 expression and CD8 positive TILs in CS cases treated at our Institution.
Design(s): A total of 81 cases: 68 uterine (84%), 10 ovarian (12.3%), 1 fallopian tube (1.2%) and 2 primary peritoneal (2.5%) were identified from our Pathology Department database after IRB approval. Pathology slides from all cases were reviewed, original diagnosis was confirmed and areas with the highest TILs were identified. 3 mm tissue microarrays were constructed from formalin-fixed, paraffin embedded tissue from areas with highest TILs and immunostaining for PD-L1 and CD8 was performed. PD-L1 was scored using Tumor Proportion Score (TPS) and Combined Positive Score (CPS) with either TPS or CPS >=1 considered positive. Cases were classified as CD8- (< 5 CD8+ TILs/hpf), CD8+ (>=5 CD8+ TILs/hpf) and CD8HIGH (>25 CD8+ TILs/hpf). We further subclassified the cases into four TME groups based on PD-L1 expression and CD8+ TILs: 1) PD-L1+/CD8+, 2) PD-L1+/CD8-, 3) PD-L1- /CD8+ and 4) PD-L1-/CD8- (Fig. 1). Clinical follow-up data was obtained from medical charts. Kaplan-Meier curves with log rank test were used to compare overall survival.
Result(s): Median overall survival was 37.4 months (range: 1-176 months). PD-L1 expression in tumor tissue (TPS) and microenvironment (CPS) was detected in 19.8% and 39.6% of cases, respectively. PD-L1 expression alone was not associated with difference in overall survival (p=0.28). In contrast, higher numbers of CD8+ TILs were associated with better survival (p=0.054 for >=5 CD8+ TILs/hpf and p=0.019 for >25 CD8+ TILs/hpf, Fig. 2A,B). Among the TME groups, the PD-L1+/CD8+ group showed better survival compared to those with PD-L1-/CD8- (p=0.05, Fig. 2C,D).
Conclusion(s): Our study found that higher numbers of CD8+ TILs are associated with significantly better survival in patients with CS. Although PD-L1 expression alone does not seem to impact survival, patients with expression of PD-L1 and high CD8+TILs have a survival advantage over those with negative PD-L1 and low CD8+TILs. These preliminary findings suggest TME has prognostic implications in patients with CS of the female genital tract
ISSN: 1530-0307
CID: 4856982

Amplification of MDM2 and Loss of p16 Expression: Do They Have a Role in Malignant Transformation of Ovarian Brenner Tumor?

Wang, Lucy; Allison, Douglas; Shukla, Pratibha Sharma
OBJECTIVES/OBJECTIVE:To review the significance of MDM2 and cyclin D1 expression and loss of p16 expression in malignant and borderline Brenner tumors (BTs) of the ovary. METHODS:We describe 2 new cases of ovarian BT, 1 malignant and 1 borderline. We studied MDM2, p16, and cyclin D1 expression by immunohistochemistry in the benign, borderline, and malignant components of these 2 cases and in 5 additional cases of benign BT. We also reviewed and summarized the literature on the clinical, immunohistochemical and molecular characteristics of borderline and malignant BTs (BdBTs and MBTs). RESULTS:Nuclear expression of MDM2 was seen only in the MBT. Loss of p16 expression was seen in both BdBT and MBT. Cyclin D1 expression was in proportion to the degree of malignancy. Amplification of MDM2, loss of CDKN2A (p16-encoding gene), and amplification of CCND1 (cyclin D1-encoding gene) were confirmed by commercial next-generation sequencing in the case of MBT. CONCLUSIONS:We are the first to report immunohistochemical expression of MDM2 in an MBT. Amplification of MDM2 and loss of p16 expression may have a role in malignant transformation of BT.
PMID: 32322877
ISSN: 1943-7722
CID: 4402272

Clinicopathologic analysis and morphologic variants of ovarian juvenile granulosa cell tumors [Meeting Abstract]

Vougiouklakis, T; Chiang, S; Shukla, P; Thomas, K; Barroeta, J; Schwartz, L; Linn, R; Oliva, E; Malpica, A; Snuderl, M; Jour, G; DeLair, D
Background: Juvenile granulosa cell tumors (JGCTs) are rare neoplasms associated with a favorable prognosis, however, a subset of patients develop recurrences. Morphologic overlap frequently renders a diagnostic challenge on account of the rarity of these tumors.
Design(s): A total of 29 cases from multiple institutions were identified. Select slides were reviewed by two experienced gynecologic pathologists. Paired primary and metastatic tumors were reviewed, except in two cases where only recurrent/metastatic tumors were available. All but one were pure JGCTs. Clinicopathologic features, including morphologic appearance, immunophenotype, and clinical follow-up, when available, were recorded.
Result(s): Patient age ranged from 2-65 years (mean: 23; median: 16), and tumor size from 4-34 cm (mean: 16; median: 14). Stage at presentation was: I (90%), II (5%), III (5%). Accompanied genetic disorders, Ollier disease and Donahue syndrome, were identified in two patients; the latter associated with bilateral tumors. Morphology showed at least one of these accompanied architectural patterns: Follicular (83%), solid (62%), multinodular (31%), cystic (24%) and papillary (10%). Additional recognized features included foamy/bubbly cytoplasm (70%), cells with a rhabdoid appearance (57%) and prominent cell borders (39%). Nuclear atypia was as follows: Mild (n=6), moderate (n=17), and moderate with focal severe/severe (n=6). Mitotic index ranged from 1-76/10 HPFs (mean: 12; median: 7). Inhibin (18/18), calretinin (12/12), CD99 (7/7), CD56 (4/4) and WT1 (2/2) were positive when applied. Nuclear grooves were seen in two cases, and no Call-Exner bodies were identified. Clinical follow-up was available for 20 patients (range 1-132 months), and identified four cases with recurrence. Two patients had recurrence in the ovary; one contralaterally at 26 months and one ipsilaterally after cystectomy at 2 months. The remaining two recurred in the colonic serosa. One patient with bilateral tumors died of disease one month after surgery.
Conclusion(s): JGCTs display a spectrum of morphologic features with variable mitotic activity and nuclear atypia. Recurrent/metastatic disease developed in 20% of patients with available follow-up and 5% died (14% and 3%, respectively, in total series). Recognition of these growth patterns and variable morphology is critical to render the correct diagnosis. Additional outcome data will be forthcoming
ISSN: 1530-0285
CID: 4471172

Recurrent chromatin remodeling pathway mutations identified in ovarian juvenile granulosa cell tumors [Meeting Abstract]

Vougiouklakis, T; Vasudevaraja, V; Shen, G; Feng, X; Chiang, S; Barroeta, J; Thomas, K; Schwartz, L; Linn, R; Oliva, E; Shukla, P; Malpica, A; DeLair, D; Snuderl, M; Jour, G
Background: The somatic missense mutation FOXL2 c.C402G (p.C134W) is harbored in 95-97% of adult granulosa cell tumors (AGCTs) and functions as a pathognomonic oncogenic driver. More recently, KMT2D and TERT promoter mutations have been reported to associate with recurrence in AGCTs. While the molecular pathogenesis of AGCTs has been well investigated, comprehensive genomic analysis of juvenile granulosa cell tumors (JGCTs) is currently lacking.
Design(s): A total of seventeen (n=17) JGCTs were selected for this study. Cases were selected and analyzed based on JGCT histomorphology and lack of FOXL2 c.C402G (p.C134W) mutational status. Slides were reviewed by two experienced gynecologic pathologists. Formalin-fixed paraffin embedded (FFPE) tissues were subjected to DNA extraction for next generation sequencing (NGS) using our customized NGS580 panel targeting all exonic and select intronic areas in 580 cancer related genes. Matched tumors against normal pools were analyzed and manually curated to filter out single nucleotide polymorphisms (SNPs) and retain pathogenic variants by a molecular pathologist.
Result(s): Clinical information and follow-up was available for eleven patients. Age at diagnosis ranged from 13 to 65 years of age (median: 28). Fifteen cases (n=15) harbored callable mutations while 2 cases only had copy number (CN) losses. Recurrent mutational events were identified in KMT2C (73%), RECQL4 (67%), FANCD2 (67%), KMT2D (53%), and RAD21 (47%). Recurrent FANCD2 c.1278-1278del (p.L426fs) frameshift deletions were identified in ten of fifteen cases (67%), and RAD21 c.A49T (p.I17F) single nucleotide variants (SNVs) in seven of fifteen cases (47%). Deleterious events included PALB2 in two cases (13%). Recurrent homozygous CN losses in ATR (n=3), CDKN2A (n=2), SUFU (n=3), RB1 (n=4) and NF1 (n=3) were present in up to 30% of the cases. EP400 and EGFR CN gains were seen in two cases [Figure 1]. The tumor mutational burden (TMB) ranged from 2.85 to 33.74 mut/mb. Four cases (27%) with a high TMB (>16.0 mut/mb; median cutoff) were associated with mutations in CD79A (p.A32G). One case with FIGO stage II and one metastatic to the mesentery were also associated with KMT2D mutations. (Figure presented)
Conclusion(s): Our findings suggest that JGCTs shows a distinct genomic landscape compared to AGCTs. Alterations affecting chromatin remodeling and hedgehog signaling pathways contribute to the pathogenesis of JGCTs. These findings provide novel insight into the pathogenesis of a rare entity
ISSN: 1530-0285
CID: 4471182

Inflammatory Myofibrobalstic Tumor in Female Genital Tract

Shukla, Pratibha Sharma; Mittal, Khushbakhat
CONTEXT/BACKGROUND:- Inflammatory myofibroblastic tumor is a mesenchymal neoplasm of low malignant potential. It was first described in lung, but is known to occur in many extrapulmonary sites including female genital organs, most commonly the uterus. It has a high recurrence rate and a low risk for metastasis. A more recently described aggressive variant, epithelioid myofibroblastic sarcoma with a predilection for the abdominal cavity of males, has also been recently reported to occur in ovary. This tumor is composed of spindled and epithelioid myofibroblasts in a variably myxoid stroma and commonly shows a fascicular growth pattern with positive staining for desmin, smooth muscle actin, and CD10, which may mimic a smooth muscle or endometrial stromal neoplasm. In the female genital tract it has the potential for being misdiagnosed as a leiomyoma, endometrial stromal tumor, or as a myxoid leiomyosarcoma, resulting in undertreatment or overtreatment. It harbors rearrangements in the ALK gene, resulting in abnormal expression of ALK protein. Immunostaining for ALK is a helpful diagnostic tool. OBJECTIVE:- To provide a brief review of clinical, histologic, immunohistochemical, and molecular features of inflammatory myofibroblastic tumor with emphasis on possible diagnostic pitfalls in the female genital tract. DATA SOURCES/METHODS:- Review of pertinent literature on inflammatory myofibroblastic tumor occurring in the female genital tract and personal experience of the authors. CONCLUSIONS:- Inflammatory myofibroblastic tumor in the female genital tract can mimic other more common benign and malignant tumors like leiomyoma, leiomyosarcoma, and endometrial stromal sarcoma. Familiarity with clinical and histologic features and use of ALK immunostaining can be critical for correct diagnosis.
PMID: 29965784
ISSN: 1543-2165
CID: 3186042