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Book: Tumors of the cervix, vagina, and vulva

Nucci, Marisa R. / Crum, Christopher P. / Howitt, Brooke E. / Parra-Herran, Carlos

(AFIP atlas of tumor and non-tumor pathology ; Fifth series, Fascicle 14)

2023

Author's details	by Marisa R. Nucci, Christopher P. Crum, Brooke E. Howitt, Carlos Parra-Herran
Series title	AFIP atlas of tumor and non-tumor pathology ; Fifth series, Fascicle 14 AFIP atlases of tumor and non-tumor pathology
Collection	AFIP atlases of tumor and non-tumor pathology
Language	English
Size	XVIII, 367 Seiten, Illustrationen
Publisher	American Registry of Pathology
Publishing place	Arlington, Virginia
Publishing country	United States
Document type	Book
HBZ-ID	HT030033684
ISBN	978-1-933477-26-8 ; 1-933477-26-1
Database	Catalogue ZB MED Medicine, Health

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2023 A 768	available for loan (reading room)	Lesesaal EG

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Article ; Online: From morphology to methylome: epigenetic studies of Müllerian mesonephric-like adenocarcinoma reveal similarities to cervical mesonephric adenocarcinoma

Lin, Lawrence H / Howitt, Brooke E / Kolin, David L

The Journal of pathology

2024

Abstract: Mesonephric adenocarcinomas (MAs) and mesonephric-like adenocarcinomas (MLAs) are rare, aggressive neoplasms that arise in the gynecologic tract and show overlapping morphologic, immunohistochemical, and molecular features. While MAs occur in the cervix ... ...

Abstract	Mesonephric adenocarcinomas (MAs) and mesonephric-like adenocarcinomas (MLAs) are rare, aggressive neoplasms that arise in the gynecologic tract and show overlapping morphologic, immunohistochemical, and molecular features. While MAs occur in the cervix and are thought to arise from mesonephric remnants, MLAs occur in the endometrium and ovary and are believed to originate from transdifferentiation of Müllerian lesions. Both MAs and MLAs show a variety of architectural patterns, exhibit frequent expression of GATA3 by immunohistochemistry, and harbor KRAS mutations. In a recent article published in The Journal of Pathology, Kommoss and colleagues used DNA methylation profiling to extend these similarities and showed that MLAs and MAs cluster together based on their epigenetic signatures and are epigenetically distinct from other Müllerian adenocarcinomas. They also showed that MLAs and MAs harbor a high number of global copy number alterations. This study provides evidence that MLAs more closely resemble MAs than Müllerian carcinomas on an epigenetic level. As a result, the authors argue that MLA should be renamed 'mesonephric-type adenocarcinoma.' Further research is needed to establish the relationship between these two entities, their etiology, and pathogenesis. © 2024 The Pathological Society of Great Britain and Ireland.
Language	English
Publishing date	2024-04-09
Publishing country	England
Document type	Journal Article
ZDB-ID	3119-7
ISSN	1096-9896 ; 0022-3417
ISSN (online)	1096-9896
ISSN	0022-3417
DOI	10.1002/path.6285
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Article ; Online: Practical Issues and Updates in Gynecologic Pathology.

Howitt, Brooke E

Surgical pathology clinics

2019 Volume 12, Issue 2, Page(s) xi–xii

Language	English
Publishing date	2019-05-16
Publishing country	United States
Document type	Editorial
ISSN	1875-9157
ISSN (online)	1875-9157
DOI	10.1016/j.path.2019.03.001
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Article ; Online: Specific Pathology Features Enrich Selection of Endometrial Carcinomas for POLE Testing.

Keyhanian, Kianoosh / Han, Lucy / Howitt, Brooke E / Longacre, Teri

The American journal of surgical pathology

2023 Volume 48, Issue 3, Page(s) 292–301

Abstract: Identification of ultramutated/ POLE -mutated endometrial carcinomas ( POLEM ECs) has important implications given its association with better prognosis. However, POLE mutation testing is not widely available. Our objective was to evaluate POLEM ECs ... ...

Abstract	Identification of ultramutated/ POLE -mutated endometrial carcinomas ( POLEM ECs) has important implications given its association with better prognosis. However, POLE mutation testing is not widely available. Our objective was to evaluate POLEM ECs versus POLE wild-type ( POLEWT ) ECs, within a cohort of consultation cases with features suggestive of an ultramutated phenotype. Consultation cases of EC that had undergone POLE hotspot mutation testing over a 3.5-year period were included. Tumor morphology and immunohistochemistry were reviewed for both groups. Chi-square test and t test were used for statistical analysis. Of 25 consultation cases, 12 harbored a POLE mutation (48%) and 13 were wild-type (52%). Patients with POLEM ECs were younger (59 vs. 71.3 y; P =0.01). Ambiguous histomorphology (5/12 vs. 1/13; P =0.04) and the presence of more than rare bizarre nuclei (8/12 vs. 2/12; P =0.01) differed significantly between POLEM and POLEWT ECs, respectively. In the POLEM group, one case (1/12) demonstrated PMS2 loss, and one (1/12) showed subclonal MLH1/PMS2 loss. Among POLEWT ECs, 3/13 (23%) showed MLH1/PMS2 loss. p53 was subclonally overexpressed in 4/10 POLEM and 1/13 POLEWT cases ( P =0.06). Mutant p53 patterns were seen in 1/10 POLEM versus 6/13 of POLEWT ECs, respectively ( P =0.06). Within our cohort, the specificity of ambiguous histomorphology, bizarre nuclei, subclonal biomarker expression, and marked tumor-infiltrating lymphocytes for POLEM EC was 83%, 80%, 80%, and 71%, respectively. Where universal POLE testing is not available, these data suggest that morphologic screening (particularly ambiguous histomorphology and the presence of more than rare bizarre nuclei) can be useful for selective enrichment of ECs for POLE testing.
MeSH term(s)	Female ; Humans ; Carcinoma, Endometrioid/pathology ; Tumor Suppressor Protein p53/genetics ; Mismatch Repair Endonuclease PMS2/genetics ; Endometrial Neoplasms/pathology ; Prognosis ; Mutation ; Poly-ADP-Ribose Binding Proteins/genetics
Chemical Substances	Tumor Suppressor Protein p53 ; Mismatch Repair Endonuclease PMS2 (EC 3.6.1.3) ; Poly-ADP-Ribose Binding Proteins
Language	English
Publishing date	2023-12-08
Publishing country	United States
Document type	Journal Article
ZDB-ID	752964-8
ISSN	1532-0979 ; 0147-5185
ISSN (online)	1532-0979
ISSN	0147-5185
DOI	10.1097/PAS.0000000000002165
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Zs.A 1356: Show issues

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Article: SMARCA4 loss irrelevant for

Wagner, Samantha Kay / Moon, Ashley S / Howitt, Brooke E / Renz, Malte

Gynecologic oncology reports

2023 Volume 50, Page(s) 101305

Abstract: Clear cell carcinomas are rare and relatively chemo-insensitive ovarian cancers with a characteristic molecular pathogenesis. Alterations ... ...

Abstract	Clear cell carcinomas are rare and relatively chemo-insensitive ovarian cancers with a characteristic molecular pathogenesis. Alterations in
Language	English
Publishing date	2023-11-14
Publishing country	Netherlands
Document type	Case Reports
ZDB-ID	2818505-5
ISSN	2352-5789
ISSN	2352-5789
DOI	10.1016/j.gore.2023.101305
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Article ; Online: Nuclear β-Catenin Expression in the Context of Abnormal p53 Expression Indicates a Nonserous Histotype in Endometrial Carcinoma.

Keyhanian, Kianoosh / Yang, Eric J / Howitt, Brooke E

International journal of gynecological pathology : official journal of the International Society of Gynecological Pathologists

2022 Volume 42, Issue 5, Page(s) 435–442

Abstract: The interobserver reproducibility is poor for histotyping within the p53-abnormal molecular category of endometrial carcinomas (ECs); therefore, biomarkers that improve histologic classification are useful. β-catenin has been proposed to have prognostic ... ...

Abstract	The interobserver reproducibility is poor for histotyping within the p53-abnormal molecular category of endometrial carcinomas (ECs); therefore, biomarkers that improve histologic classification are useful. β-catenin has been proposed to have prognostic significance in specific clinicopathologic and molecular contexts. The diagnostic utility for β-catenin expression patterns in determining the histotype of p53-abnormal ECs has not been well studied. We identified ECs molecularly classified as "p53-abnormal." The p53-abnormal classification was assigned when (1) no POLE exonuclease domain hotspot mutations identified, (2) mismatch-repair protein expression was retained, and (3) abnormal p53 expression (null or overexpression) was present. Morphology was re-reviewed and β-catenin immunohistochemistry was scored as abnormal (nuclear) or normal (membranous, non-nuclear). Eighty ECs were identified in the "p53-abnormal" category; 27 (33.75%) were uterine serous carcinomas, and 53 were of nonserous histotype: 28 uterine carcinosarcomas (35%), 16 endometrioid carcinomas (20%), 2 clear cell carcinomas (2.5%), and 7 high-grade EC with ambiguous morphology (8.75%). All 27 uterine serous carcinomas demonstrated membranous β-catenin staining. Of the 53 nonserous ECs, 11 (21%) showed abnormal β-catenin expression: 6 endometrioid carcinomas, 4 uterine carcinosarcoma, and 1 high-grade EC with ambiguous morphology. The specificity of abnormal β-catenin expression for nonserous EC is high (100%) but the sensitivity is low (21%) with positive and negative predictive values of 100% and 60%, respectively. Our data shows that abnormal β-catenin expression in the context of p53-abnormal EC is highly specific, but not sensitive, for nonserous ECs and may be of value as part of a panel in classifying high-grade EC, particularly to exclude uterine serous carcinoma when nuclear staining is present.
MeSH term(s)	Female ; Humans ; Carcinoma, Endometrioid/diagnosis ; Carcinoma, Endometrioid/genetics ; Carcinoma, Endometrioid/metabolism ; beta Catenin/genetics ; beta Catenin/metabolism ; Tumor Suppressor Protein p53/genetics ; Tumor Suppressor Protein p53/metabolism ; Reproducibility of Results ; Biomarkers, Tumor/genetics ; Biomarkers, Tumor/metabolism ; Endometrial Neoplasms/diagnosis ; Endometrial Neoplasms/genetics ; Endometrial Neoplasms/metabolism ; Uterine Neoplasms/pathology
Chemical Substances	beta Catenin ; Tumor Suppressor Protein p53 ; Biomarkers, Tumor
Language	English
Publishing date	2022-10-11
Publishing country	United States
Document type	Journal Article
ZDB-ID	604859-6
ISSN	1538-7151 ; 0277-1691
ISSN (online)	1538-7151
ISSN	0277-1691
DOI	10.1097/PGP.0000000000000923
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Zs.A 1814: Show issues

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Article ; Online: Update on SWI/SNF-related gynecologic mesenchymal neoplasms: SMARCA4-deficient uterine sarcoma and SMARCB1-deficient vulvar neoplasms.

Howitt, Brooke E / Folpe, Andrew L

Genes, chromosomes & cancer

2020 Volume 60, Issue 3, Page(s) 190–209

Abstract: Our knowledge regarding the role of genes encoding the chromatin remodeling switch/sucrose non-fermenting (SWI/SNF) complex in the initiation and progression of gynecologic malignancies continues to evolve. This review focuses on gynecologic tumors in ... ...

Abstract	Our knowledge regarding the role of genes encoding the chromatin remodeling switch/sucrose non-fermenting (SWI/SNF) complex in the initiation and progression of gynecologic malignancies continues to evolve. This review focuses on gynecologic tumors in which the sole or primary genetic alteration is in SMARCA4 or SMARCB1, two members of the SWI/SNF chromatin remodeling complex. In this review, we present a brief overview of the classical example of such tumors, ovarian small cell carcinoma of hypercalcemic type, and then a detailed review and update of SMARCB1-deficient and SMARCA4-deficient tumors of the uterus and vulva.
MeSH term(s)	Chromatin Assembly and Disassembly ; Chromosomal Proteins, Non-Histone/genetics ; Chromosomal Proteins, Non-Histone/metabolism ; DNA Helicases/deficiency ; DNA Helicases/genetics ; DNA Helicases/metabolism ; Female ; Humans ; Nuclear Proteins/deficiency ; Nuclear Proteins/genetics ; Nuclear Proteins/metabolism ; Ovarian Neoplasms/genetics ; Ovarian Neoplasms/metabolism ; SMARCB1 Protein/deficiency ; SMARCB1 Protein/genetics ; SMARCB1 Protein/metabolism ; Sarcoma/genetics ; Sarcoma/metabolism ; Transcription Factors/deficiency ; Transcription Factors/genetics ; Transcription Factors/metabolism ; Uterine Neoplasms/genetics ; Uterine Neoplasms/metabolism ; Vulvar Neoplasms/genetics ; Vulvar Neoplasms/metabolism
Chemical Substances	Chromosomal Proteins, Non-Histone ; Nuclear Proteins ; SMARCB1 Protein ; SMARCB1 protein, human ; SWI-SNF-B chromatin-remodeling complex ; Transcription Factors ; SMARCA4 protein, human (EC 3.6.1.-) ; DNA Helicases (EC 3.6.4.-)
Language	English
Publishing date	2020-12-14
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	1018988-9
ISSN	1098-2264 ; 1045-2257
ISSN (online)	1098-2264
ISSN	1045-2257
DOI	10.1002/gcc.22922
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Zs.A 2966: Show issues

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Article ; Online: Well-differentiated lipomatous neoplasms with p53 alterations: a clinicopathological and molecular study of eight cases with features of atypical pleomorphic lipomatous tumour.

Hammer, Phoebe M / Kunder, Christian A / Howitt, Brooke E / Charville, Gregory W

Histopathology

2022 Volume 80, Issue 4, Page(s) 656–664

Abstract: Aims: Well-differentiated lipomatous neoplasms encompass a broad spectrum of benign and malignant tumours, many of which are characterised by recurrent genetic abnormalities. Although a key regulator of p53 signalling, MDM2, is characteristically ... ...

Abstract	Aims: Well-differentiated lipomatous neoplasms encompass a broad spectrum of benign and malignant tumours, many of which are characterised by recurrent genetic abnormalities. Although a key regulator of p53 signalling, MDM2, is characteristically amplified in well-differentiated liposarcoma, recurrent abnormalities of p53 itself have not been reported in well-differentiated adipocytic neoplasms. Here, we present a series of well-differentiated lipomatous tumours characterised by p53 alterations and histological features in keeping with atypical pleomorphic lipomatous tumour (APLT). Methods and results: We reviewed the morphological, immunohistochemical and molecular genetic features of eight lipomatous tumours with p53 alterations. Four tumours arose in the thigh, and one case each arose in the shoulder, calf, upper back, and subclavicular regions; six tumours were deep/subfascial and two were subcutaneous. Relevant clinical history included two patients with Li-Fraumeni syndrome. Morphologically, all cases showed well-differentiated adipocytes with prominent nuclear pleomorphism, limited mitotic activity, and no tumour cell necrosis. All cases were negative for MDM2 overexpression and amplification as determined with immunohistochemistry and fluorescence in-situ hybridisation, respectively. Immunohistochemically, p16 was diffusely overexpressed in all cases; seven tumours (88%) showed abnormal loss of Rb and p53. TP53 mutation or deletion was identified in four of six tumours evaluated with exon-targeted hybrid capture-based massively parallel sequencing; RB1 mutation or deletion was present in five of six cases. Conclusions: We present a series of eight well-differentiated lipomatous neoplasms characterised by p53 alterations in addition to Rb loss and histological features of APLT. These findings suggest that impaired p53 signalling may contribute to the pathogenesis of APLT in a subset of cases.
MeSH term(s)	Adolescent ; Aged ; Child ; Female ; Humans ; Liposarcoma/genetics ; Liposarcoma/pathology ; Male ; Middle Aged ; Retrospective Studies ; Soft Tissue Neoplasms/genetics ; Soft Tissue Neoplasms/pathology ; Tumor Suppressor Protein p53/genetics
Chemical Substances	Tumor Suppressor Protein p53
Language	English
Publishing date	2022-01-05
Publishing country	England
Document type	Journal Article
ZDB-ID	131914-0
ISSN	1365-2559 ; 0309-0167
ISSN (online)	1365-2559
ISSN	0309-0167
DOI	10.1111/his.14593
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Zs.A 1328: Show issues

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Article ; Online: Favorable Outcome of High-grade Endometrial Stromal Sarcoma in an Adolescent.

Hu, Benjamin / Howitt, Brooke E / Cizek, Stephanie / Diver, Elisabeth / Hiniker, Susan / Crane, Jacquelyn / Daldrup-Link, Heike / Spunt, Sheri L

Journal of pediatric hematology/oncology

2024

Abstract: High-grade endometrial stromal sarcoma is a rare and aggressive soft tissue tumor characterized by YWHAE::NUTM2A/B translocations, diagnosis at a median of 50-60 years, and a poor prognosis (overall survival 30%-40%). We describe a 16-year-old patient ... ...

Abstract	High-grade endometrial stromal sarcoma is a rare and aggressive soft tissue tumor characterized by YWHAE::NUTM2A/B translocations, diagnosis at a median of 50-60 years, and a poor prognosis (overall survival 30%-40%). We describe a 16-year-old patient with high-grade endometrial stromal sarcoma and regional nodal and pulmonary metastases who is a long-term survivor after grossly complete tumor resection, intensive chemotherapy, and pelvic radiotherapy. We discovered a previously undescribed YWHAE::NUTM2E translocation in the tumor. Our patient's favorable outcome suggests that intensive multimodality therapy with curative intent is appropriate for young patients with high-grade endometrial stromal sarcoma and highlights the importance of fertility preservation.
Language	English
Publishing date	2024-04-26
Publishing country	United States
Document type	Journal Article
ZDB-ID	1231152-2
ISSN	1536-3678 ; 1077-4114 ; 0192-8562
ISSN (online)	1536-3678
ISSN	1077-4114 ; 0192-8562
DOI	10.1097/MPH.0000000000002865
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Zs.A 1537: Show issues

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Article ; Online: Endometrioid Endometrial RNA Index Predicts Recurrence in Stage I Patients.

Nief, Corrine A / Hammer, Phoebe M / Wang, Aihui / Charu, Vivek / Tanweer, Amina / Litkouhi, Babak / Kidd, Elizabeth / Gentles, Andrew J / Howitt, Brooke E

Clinical cancer research : an official journal of the American Association for Cancer Research

2024

Abstract: Purpose: Risk prediction with genomic and transcriptomic data has the potential to improve patient outcomes by enabling clinicians to identify patients requiring adjuvant treatment approaches, while sparing low-risk patients from unnecessary ... ...

Abstract	Purpose: Risk prediction with genomic and transcriptomic data has the potential to improve patient outcomes by enabling clinicians to identify patients requiring adjuvant treatment approaches, while sparing low-risk patients from unnecessary interventions. Endometrioid endometrial carcinoma (EEC) is the most common cancer in women in developed countries, and rates of endometrial cancer are increasing. Experimental design: We collected a 105-patient case-control cohort of stage I EEC comprised of 45 patients who experienced recurrence less than 6 years after excision, and 60 FIGO grade matched controls without recurrence. We first utilized two RNA based, previously validated machine learning approaches, namely EcoTyper and Complexity Index in Sarcoma (CINSARC). We developed Endometrioid Endometrial RNA Index (EERI) which uses RNA expression data from 46 genes to generate a personalized risk score for each patient. EERI was trained on our 105-patient cohort and tested on a publicly available cohort of 263 stage I EEC patients. Results: EERI was able to predict recurrences with 94% accuracy in the training set and 81% accuracy in the test set. In the test set, patients assigned as EERI high-risk were significantly more likely to experience recurrence (30%) than the EERI low-risk group (1%) with a hazard ratio of 9.9 (95% CI 4.1-23.8, P <0.001). Conclusions: Tumors with high-risk genetic features may require additional treatment or closer monitoring and are not readily identified using traditional clinicopathologic and molecular features. EERI performs with high sensitivity and modest specificity, which may benefit from further optimization and validation in larger independent cohorts.
Language	English
Publishing date	2024-04-26
Publishing country	United States
Document type	Journal Article
ZDB-ID	1225457-5
ISSN	1557-3265 ; 1078-0432
ISSN (online)	1557-3265
ISSN	1078-0432
DOI	10.1158/1078-0432.CCR-23-3158
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