Publications by authors named "Karen L Talia"

24 Publications

  • Page 1 of 1

Molecular subclassification of vulvar squamous cell carcinoma: reproducibility and prognostic significance of a novel surgical technique.

Int J Gynecol Cancer 2022 Aug 1;32(8):977-985. Epub 2022 Aug 1.

Division of Gynecologic Pathology, University of Leipzig, Leipzig, Germany.

Objectives: Vulvar squamous cell carcinoma is subclassified into three prognostically relevant groups: (i) human papillomavirus (HPV) associated, (ii) HPV independent p53 abnormal (mutant pattern), and (iii) HPV independent p53 wild type. Immunohistochemistry for p16 and p53 serve as surrogates for HPV viral integration and mutational status. We assessed the reproducibility of the subclassification based on p16 and p53 immunohistochemistry and evaluated the prognostic significance of vulvar squamous cell carcinoma molecular subgroups in a patient cohort treated by vulvar field resection surgery.

Methods: In this retrospective cohort study, 68 cases treated by vulvar field resection were identified from the Leipzig School of Radical Pelvic Surgery. Immunohistochemistry for p16 and p53 was performed at three different institutions and evaluated independently by seven pathologists and two trainees. Tumors were classified into one of four groups: HPV associated, HPV independent p53 wild type, HPV independent p53 abnormal, and indeterminate. Selected cases were further interrogated by (HPV RNA in situ hybridization, sequencing).

Results: Final subclassification yielded 22 (32.4%) HPV associated, 41 (60.3%) HPV independent p53 abnormal, and 5 (7.3%) HPV independent p53 wild type tumors. Interobserver agreement (overall Fleiss' kappa statistic) for the four category classification was 0.74. No statistically significant differences in clinical outcomes between HPV associated and HPV independent vulvar squamous cell carcinoma were observed.

Conclusion: Interobserver reproducibility of vulvar squamous cell carcinoma subclassification based on p16 and p53 immunohistochemistry may support routine use in clinical practice. Vulvar field resection surgery showed no significant difference in clinical outcomes when stratified based on HPV status.
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http://dx.doi.org/10.1136/ijgc-2021-003251DOI Listing
August 2022

Neuroendocrine Neoplasia of the Female Genital Tract.

Surg Pathol Clin 2022 Jun 18;15(2):407-420. Epub 2022 May 18.

Department of Cellular Pathology, Birmingham Women's Hospital, Birmingham, United Kingdom.

Neuroendocrine neoplasia is relatively uncommon in the female genital tract (FGT) and occurs at any site, most often the ovary and cervix. A unified dichotomous nomenclature, introduced by the World Health Organization Classification of Tumors in all fifth edition volumes, divides neuroendocrine neoplasms (NENs) into well-differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinomas (NECs). The term carcinoid tumor is retained in the ovary and represents the commonest FGT NEN. NEC is most common in the cervix and is usually admixed with another human papillomavirus-associated epithelial neoplasm. Despite shared neuroendocrine differentiation, NET and NEC show diverse etiology, morphology, and clinical behavior.
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http://dx.doi.org/10.1016/j.path.2022.02.012DOI Listing
June 2022

Microscopic Sertoliform Sex Cord Proliferations: A Rare Incidental Finding Associated With Endometriosis and Ovarian Epithelial Neoplasia.

Int J Gynecol Pathol 2022 Mar 14. Epub 2022 Mar 14.

Department of Pathology, Royal Women's Hospital and VCS Foundation, Melbourne, Victoria, Australia (K.L.T.) Department of Pathology, Belfast Health and Social Care Trust, Belfast, UK (W.G.M.).

Microscopic sex cord proliferations are a rare incidental finding seen in association with ovarian and uterine stromal or epithelial neoplasms and more uncommonly non-neoplastic conditions such as endometriosis and adenomyosis. They may also occur in the absence of other pathology, as an incidental finding in the ovaries of pregnant women and in heterotopic locations such as the fallopian tube. Most reports of this phenomenon describe adult granulosa cell tumor-like morphology. Herein, we describe 4 cases of microscopic sex cord proliferations with Sertoliform features, occurring in the stromal component of endometriosis or in the wall of an epithelial ovarian neoplasm; 2 of the patients with endometriosis had concurrent endometrioid adenocarcinoma (1 uterine corpus, 1 ovary). The proliferations were positive with sex cord markers inhibin and calretinin. As far as we are aware, such Sertoliform proliferations have not been reported previously in endometriosis and have only rarely been described in association with ovarian epithelial neoplasia. It is likely that such proliferations represent a benign non-neoplastic phenomenon. Awareness of this phenomenon is important in order to avoid misdiagnosis as a sex cord or other neoplasm. In reporting this unusual phenomenon, we review incidental sex cord and sex cord-like proliferations in the female genital tract.
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http://dx.doi.org/10.1097/PGP.0000000000000873DOI Listing
March 2022

HPV42-associated Seborrhoeic Keratosis-like Lesion of the Cervix: First Reported Case With High-grade Morphology.

Int J Gynecol Pathol 2021 Nov 12. Epub 2021 Nov 12.

From the Department of Pathology, Royal Women's Hospital (K.L.T.); VCS Pathology, VCS Foundation (K.L.T., D.H.); Department of Biochemistry and Pharmacology, University of Melbourne (D.H.), Melbourne, Victoria, Australia; Department of Pathology, Brighton and Sussex University Hospitals NHS Trust, Brighton (S.R.); School of Pharmacy and Biomedical Sciences, University of Portsmouth, Portsmouth (S.R.); Department of Pathology, University of Malaya, Kuala Lumpur, Malaysia (D.H.); and Department of Pathology, Belfast Health and Social Care Trust, Belfast (W.G.M.), UK.

Seborrheic keratosis-like lesion (SKLL) is an extremely rare, morphologically distinct lesion occurring in the cervix and vagina that differs histologically from usual squamous intraepithelial lesions in these sites, by bearing close resemblance to cutaneous seborrheic keratosis and lacking koilocytosis. Like many vulvar seborrheic keratoses, which are associated with low-risk human papillomavirus (HPV), an association between SKLL and low-risk HPV is suggested based on the identification of HPV42, regarded as a low-risk genotype, in 4 of 8 reported cases. We report a further HPV42-associated SKLL of the cervix which differs from the previously reported cases by the presence of high-grade morphology and block-type p16 immunoreactivity. This novel finding challenges the classification of HPV42 as a low-risk genotype and expands the reported morphologic spectrum of SKLL, suggesting that they may not always be clinically indolent.
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http://dx.doi.org/10.1097/PGP.0000000000000835DOI Listing
November 2021

Seborrheic Keratosis-Like Lesion of the Cervix: First Report of the Cytological Features of a Low-Risk HPV 42-Associated Lesion.

Acta Cytol 2021 22;65(5):448-452. Epub 2021 Jul 22.

Department of Pathology, Belfast Health and Social Care Trust, Belfast, United Kingdom.

Introduction: Seborrheic keratosis-like lesion of the cervix and vagina is a rare lesion and shows similar morphology to vulvar seborrheic keratosis; 3 of the 7 previously reported cases were associated with low-risk human papillomavirus (HPV) type 42. We report a case of seborrheic keratosis-like lesion of the cervix and provide the first description of the cytological features of this lesion.

Case Presentation: A woman in her late forties presented with postcoital bleeding. She had a cervical screening test following which she underwent cervical biopsy, endocervical and endometrial curettage, large loop excision of the transformation zone of the cervix, and hysterectomy.

Results: The liquid-based cytology preparation showed cohesive groups of mildly atypical squamoid cells with a spindle cell morphology, mildly increased nuclear to cytoplasmic ratio, prominent nucleoli, and occasional nuclear grooves. No koilocytes were identified. Molecular genotyping revealed positivity for HPV type 42.

Discussion/conclusion: This represents the first description of the cytological features of a seborrheic keratosis-like lesion of the cervix, which are distinctive and unusual. Whilst the mild squamous atypia raised the possibility of a low-grade squamous intraepithelial lesion, no koilocytes were identified. The association in our case with a low-risk HPV type, HPV 42, provides further evidence for a role of this HPV type in the pathogenesis of these lesions.
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http://dx.doi.org/10.1159/000517479DOI Listing
September 2021

Outcomes of women with positive oncogenic HPV and reflex cytology showing possible high-grade squamous intraepithelial lesion.

Aust N Z J Obstet Gynaecol 2021 12 19;61(6):910-917. Epub 2021 Jul 19.

Department of Oncology & Dysplasia, The Royal Women's Hospital, Parkville, Victoria, Australia.

Aim: To examine outcomes in women following cervical screening detection of oncogenic human papillomavirus (HPV), with reflex cytology showing possible high-grade squamous intraepithelial lesion (pHSIL).

Materials And Methods: A retrospective observational study of 523 women seen in the Royal Women's Hospital Colposcopy Clinic from 1 January 2018 to 31 July 2020.

Results: Two hundred eighty-two (53.9%) women had histology-confirmed HSIL, encompassing CIN2 or worse (CIN2+), including seven cancers (1.3%) and two adenocarcinoma in situ (AIS) (0.4%). In 81.2% (229/282) of women with CIN2+, this was detected on cervical biopsy at initial colposcopy, with another 8.9% (25/282) of CIN2+ detected at cervical excision following initial colposcopy and the remaining 9.9% (28/282) at follow-up colposcopy thereafter. When discordant cervical biopsy results were discussed at multidisciplinary meeting (MDM), 66.7% of women with pHSIL cytology upgraded to definite HSIL were found to have CIN2+, but only 20.8% when pHSIL cytology was retained and none when downgraded to low-grade (LSIL) or normal. No significant difference was found in the proportion of CIN2+ based on patient age above or below 40, HPV16 and/or 18 versus non 16/18, or whether discordant findings were reviewed at MDM.

Conclusions: We propose a pathway for management of women with positive oncogenic HPV and reflex pHSIL cytology. MDM review is recommended when CIN2+ is not identified on cervical biopsy at initial colposcopy. Conservative management is safe with low risk of CIN2+ when LBC prediction of pHSIL is confirmed or downgraded at MDM with no high-grade change on colposcopy or repeat cytology.
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http://dx.doi.org/10.1111/ajo.13408DOI Listing
December 2021

Ovarian mucinous and seromucinous neoplasms: problematic aspects and modern diagnostic approach.

Histopathology 2022 Jan 20;80(2):255-278. Epub 2021 Oct 20.

Department of Pathology, Belfast Health and Social Care Trust, Belfast, UK.

The morphological spectrum of primary ovarian mucinous and seromucinous tumours is broad, and presents an array of diagnostic challenges, many unique to these tumour types. This reflects the heterogeneous nature of these lesions, their varied histogenesis and evolving classification systems over recent decades, with further modification to the seromucinous category incorporated in the recently published 5th edition of the World Health Organisation (WHO) Classification of female genital tumours. In this review we provide an update on the classification of these neoplasms and discuss their histogenesis and diverse morphology, focusing on areas which are diagnostically problematic. We also cover tumour grading, differential diagnosis, immunohistochemistry, the recent elucidation of the molecular underpinnings of ovarian mucinous neoplasia and discuss the gross and intra-operative handling of these tumours. A number of diagnostic issues remain unresolved, highlighting the importance of further research on this front, as well as a multidisciplinary approach in the care of patients with ovarian mucinous and seromucinous neoplasia.
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http://dx.doi.org/10.1111/his.14399DOI Listing
January 2022

Precursor Lesions of Cervical Clear Cell Carcinoma: Evidence For Origin From Tubo-Endometrial Metaplasia.

Int J Gynecol Pathol 2022 Mar;41(2):105-112

Cervical clear cell carcinoma (CCC) is an HPV-independent tumor historically associated with in-utero exposure to diethylstilboestrol. With the cessation of diethylstilboestro use, most contemporary cases are sporadic and of uncertain pathogenesis, with no established precursor lesion. Following the detection of 3 incidental "early" (FIGO stage IA1) cervical CCCs, all of which displayed adjacent tubo-endometrial metaplasia, we examined further cases, including resection specimens, of this tumor in an attempt to delineate potential precursors. We identified tubo-endometrial metaplasia in proximity to the tumor in 5 of 5 additional primary cervical CCCs, with some tubo-endometrial glands exhibiting subtle mild cytologic atypia. This observation adds to the sparse existing literature proposing tubo-endometrial metaplasia as a precursor to sporadic cervical CCC, with possible progression via an "atypical" transitional phase to malignancy. We also review the published literature regarding possible precursor lesions of primary cervical CCC.
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http://dx.doi.org/10.1097/PGP.0000000000000785DOI Listing
March 2022

Grading of Endocervical Adenocarcinomas: Review of the Literature and Recommendations From the International Society of Gynecological Pathologists.

Int J Gynecol Pathol 2021 Mar;40(Suppl 1):S66-S74

There is a lack of consensus regarding the prognostic value of grading endocervical adenocarcinomas and currently, no universally applied, validated system for grading exists. Several grading schemes have been proposed, most incorporating an evaluation of tumor architecture and nuclear morphology and these are often based on the International Federation of Gynecology and Obstetrics (FIGO) system for endometrial endometrioid carcinoma, although some schemes modify the proportion of solid tumor required to separate grades 1 and 2 from 5% to 10%. In the absence of a validated system, we endorse this approach for most human papillomavirus-associated endocervical adenocarcinomas and, based on the available evidence, recommend that tumors with ≤10% solid growth be designated grade 1, 11% to 50% solid growth grade 2 and >50% solid growth grade 3. Tumors should be upgraded in the presence of marked nuclear atypia involving the majority (>50%) of the tumor. Grading is not recommended for human papillomavirus-independent adenocarcinomas, since no validated system has been suggested and most of these neoplasms exhibit intrinsically aggressive behavior regardless of their morphologic appearance. Importantly, grading should not be performed for gastric-type adenocarcinomas, particularly as these tumors may appear deceptively "low-grade" yet still exhibit aggressive behavior. Recently devised, validated and reproducible etiology and pattern-based tumor classification systems for endocervical adenocarcinomas appear to offer more effective risk stratification than tumor grading and, in the future, these systems may render the provision of a tumor grade redundant.
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http://dx.doi.org/10.1097/PGP.0000000000000741DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7969159PMC
March 2021

Massively parallel sequencing analysis of 68 gastric-type cervical adenocarcinomas reveals mutations in cell cycle-related genes and potentially targetable mutations.

Mod Pathol 2021 06 14;34(6):1213-1225. Epub 2020 Dec 14.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Gastric-type cervical adenocarcinoma (GCA) is an aggressive type of endocervical adenocarcinoma characterized by mucinous morphology, gastric-type mucin, lack of association with human papillomavirus (HPV) and resistance to chemo/radiotherapy. We characterized the landscape of genetic alterations in a large cohort of GCAs, and compared it with that of usual-type HPV-associated endocervical adenocarcinomas (UEAs), pancreatic adenocarcinomas (PAs) and intestinal-type gastric adenocarcinomas (IGAs). GCAs (n = 68) were subjected to massively parallel sequencing targeting 410-468 cancer-related genes. Somatic mutations and copy number alterations (CNAs) were determined using validated bioinformatics methods. Mutational data for UEAs (n = 21), PAs (n = 178), and IGAs (n = 148) from The Cancer Genome Atlas (TCGA) were obtained from cBioPortal. GCAs most frequently harbored somatic mutations in TP53 (41%), CDKN2A (18%), KRAS (18%), and STK11 (10%). Potentially targetable mutations were identified in ERBB3 (10%), ERBB2 (8%), and BRAF (4%). GCAs displayed low levels of CNAs with no recurrent amplifications or homozygous deletions. In contrast to UEAs, GCAs harbored more frequent mutations affecting cell cycle-related genes including TP53 (41% vs 5%, p < 0.01) and CDKN2A (18% vs 0%, p = 0.01), and fewer PIK3CA mutations (7% vs 33%, p = 0.01). TP53 mutations were less prevalent in GCAs compared to PAs (41% vs 56%, p < 0.05) and IGAs (41% vs 57%, p < 0.05). GCAs showed a higher frequency of STK11 mutations than PAs (10% vs 2%, p < 0.05) and IGAs (10% vs 1%, p < 0.05). GCAs harbored more frequent mutations in ERBB2 and ERBB3 (9% vs 1%, and 10% vs 0.5%, both p < 0.01) compared to PAs, and in CDKN2A (18% vs 1%, p < 0.05) and KRAS (18% vs 6%, p < 0.05) compared to IGAs. GCAs harbor recurrent somatic mutations in cell cycle-related genes and in potentially targetable genes, including ERBB2/3. Mutations in genes such as STK11 may be used as supportive evidence to help distinguish GCAs from other adenocarcinomas with similar morphology in metastatic sites.
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http://dx.doi.org/10.1038/s41379-020-00726-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8154628PMC
June 2021

Uterine Adenosarcoma Originating in Adenomyosis: Report of an Extremely Rare Phenomenon and Review of Published Literature.

Int J Gynecol Pathol 2021 Jul;40(4):342-348

Müllerian adenosarcoma is an uncommon biphasic malignant tumor most often occurring in the uterine corpus and derived from native surface endometrium. We report a case of intramural uterine adenosarcoma arising in association with adenomyosis, in the absence of tumor involving the surface endometrium. This is an extremely rare phenomenon, with only 8 other published cases of uterine corpus adenosarcoma in the absence of surface endometrial involvement, 5 originating in adenomyosis and 3 in adenomyomas. We review these cases. The current FIGO staging system for uterine adenosarcoma assumes origin from the surface endometrium and does not address the rare occurrence of intramural tumors without a surface endometrial component. Such tumors are problematic to stage and could potentially be overtreated, particularly if there is deep myometrial involvement.
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http://dx.doi.org/10.1097/PGP.0000000000000709DOI Listing
July 2021

The Evolving Spectrum of Precursor Lesions of Cervical Adenocarcinomas.

Adv Anat Pathol 2020 Sep;27(5):278-293

Department of Pathology, Belfast Health and Social Care Trust, Belfast, UK.

Modern classification schemes divide cervical adenocarcinomas into human papillomavirus (HPV)-associated and HPV-independent types. The precursor lesions of the former are well known and comprise HPV-associated (usual/endocervical) adenocarcinoma in situ (AIS) and the much less common stratified mucin-producing intraepithelial lesion (SMILE). The precursor lesions of HPV-independent cervical adenocarcinomas are much less well known, although postulated precursors of gastric-type adenocarcinoma include atypical lobular endocervical glandular hyperplasia and gastric-type AIS. In this review, we cover HPV-associated and HPV-independent precursor lesions of cervical adenocarcinomas concentrating on diagnostic criteria (morphology and immunophenotype) and differential diagnosis. We propose a uniform terminology and diagnostic criteria for precursor lesions showing intestinal differentiation with goblet cells because this may be a feature of both HPV-associated and HPV-independent AIS.
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http://dx.doi.org/10.1097/PAP.0000000000000266DOI Listing
September 2020

Endometrial Gastric (Gastrointestinal)-type Mucinous Lesions: Report of a Series Illustrating the Spectrum of Benign and Malignant Lesions.

Am J Surg Pathol 2020 03;44(3):406-419

Department of Pathology, Belfast Health and Social Care Trust, Belfast, UK.

With the recent elucidation of gastric-type lesions in the female genital tract (especially in the cervix), occasional cases of endometrial adenocarcinoma displaying gastric (gastrointestinal) differentiation have been reported, but they are currently not recognized as a distinct pathologic entity. We report 9 cases of endometrial mucinous lesions which exhibit gastric (gastrointestinal)-type features by morphology and immunohistochemistry, including 4 adenocarcinomas and 5 benign mucinous lesions, in patients aged 32 to 85. The adenocarcinomas showed gastric-type morphology in all 4 cases and goblet cells in 1, with a component of benign gastric-type mucinous glands in 1 case. Immunohistochemically, the adenocarcinomas were positive for CK7 (4/4), CEA (4/4), MUC6 (3/3), PAX8 (3/4), CK20 (2/4), CDX2 (2/4), and estrogen receptor (1/4). They were negative for Napsin A (0/3), with mutation-type p53 staining in 2/4 cases, block-type p16 positivity in 1/4, and scattered chromogranin-positive cells in 1/2. Targeted next-generation sequencing revealed nonsense mutation in RB1 gene for the case with block-positive p16. Follow-up was available in all adenocarcinoma cases and indicated aggressive behavior; 2 patients were dead of disease at follow-up of 7 months to 3 years, 1 was alive with progression at 9 months, and 1 was alive without disease at 7 months. The benign mucinous lesions (including the benign component in 1 adenocarcinoma) exhibited gastric-type morphologic features in 5/6 cases, goblet cells in 5/6, and Paneth-like neuroendocrine cells in 1/6. These benign mucinous lesions were associated with an endometrial polyp in 5/6 cases. Cytologic atypia was present in 2/6 cases and a lobular architecture resembling cervical lobular endocervical glandular hyperplasia in 4/6. Immunohistochemically, the benign mucinous lesions were positive for CK7 (5/5), CDX2 (5/6), estrogen receptor (4/5), MUC6 (4/5), CK20 (3/5), PAX8 (3/5), and CEA (2/4), with scattered chromogranin-positive cells in 4/4 cases; in all cases tested Napsin A was negative, p53 was wild-type and p16 was negative. We propose the term "endometrial gastric (gastrointestinal)-type adenocarcinoma" for this distinctive group of rare aggressive endometrial carcinomas. We believe that benign or atypical gastric (gastrointestinal)-type mucinous lesions are putative precursors for these adenocarcinomas, comparable to recognized premalignant gastric-type lesions in the cervix and the vagina. Future recognition and reporting of these gastric-type endometrial mucinous lesions will help delineate their pathogenesis and clinical significance.
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http://dx.doi.org/10.1097/PAS.0000000000001381DOI Listing
March 2020

A Clinicopathologic Study and Descriptive Analysis of "Atypical Endosalpingiosis".

Int J Gynecol Pathol 2020 May;39(3):254-260

Department of Pathology, Box Hill Hospital, Eastern Health, Melbourne, Vic., Australia (K.L.T.) Department of Anatomical Pathology, Pathology New South Wales, John Hunter Hospital, Hunter New England, NSW (L.F., J.S.), Australia Department of Pathology, Belfast Health and Social Care Trust, Belfast, UK (W.G.M.).

"Atypical endosalpingiosis" (AE) is a diagnostic term used variably among pathologists to denote peritoneal lesions exhibiting architectural changes and/or cytologic atypia intermediate between endosalpingiosis and primary peritoneal serous borderline tumor (SBT). AE is a contentious entity and is not recognized in the current World Health Organisation Classification. We report a series of 10 cases classified as AE, in attempt to further characterize this lesion. The patients ranged in age from 24 to 72 yr (mean, 39.7 yr) and the commonest presenting complaint was abdominal pain. Operative findings usually comprised small peritoneal nodules and/or fibrous adhesions, predominantly involving the pelvis. The lesions were either mesothelial or submesothelial in location and typically exhibited mixed tubular and papillary architecture, sometimes with minor components of solid, cribriform or single cell growth. Epithelial multilayering was present in all cases but usually involved <25% of the lesion. There was mild nuclear atypia and mitoses were infrequent or absent. No infiltrative growth was seen. The stroma was usually inflamed and psammoma bodies were consistently present. Features which prompt a diagnosis of AE rather than endosalpingiosis include architectural alterations, usually in the form of papillae, epithelial multilayering, and mild nuclear atypia. While the extent of these findings is often less than occurs in primary peritoneal SBT or in extraovarian implants in association with an ovarian SBT, robust histologic criteria for distinction of AE from SBT do not exist. Despite this, the term AE may be of use when dealing with atypical peritoneal proliferations resembling SBT but which are limited in extent or fall just short of criteria for an unequivocal diagnosis of primary peritoneal SBT. In our series, lesions diagnosed as AE did not result in adverse clinical outcome (follow-up in 8 patients from 4 to 84 mo). Further study is required to determine whether a diagnostically reproducible and clinically relevant intermediate lesion exists between endosalpingiosis and SBT.
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http://dx.doi.org/10.1097/PGP.0000000000000600DOI Listing
May 2020

Expression of Markers of Müllerian Clear Cell Carcinoma in Primary Cervical and Vaginal Gastric-type Adenocarcinomas.

Int J Gynecol Pathol 2019 May;38(3):276-282

Department of Pathology, Box Hill Hospital, Melbourne, Vic., Australia (K.L.T.) Department of Clinical Pathology, Pamela Youde Nethersole Eastern Hospital, Hong Kong, China (R.W.-C.W.) Department of Pathology, Belfast Health and Social Care Trust, Belfast, Northern Ireland, UK (W.G.M.).

The incidence of cervical adenocarcinoma, both absolute and relative to squamous cell carcinoma, is increasing. Most cervical adenocarcinomas are human papillomavirus associated, although non-human papillomavirus-associated neoplasms exist; the latter include gastric-type adenocarcinoma (GAS) and clear cell carcinoma (CCC). Histologically, these 2 tumors may superficially resemble one other and although morphologic evaluation usually permits a correct diagnosis, immunohistochemistry may be required to resolve diagnostic uncertainty, especially in a small biopsy specimen. Markers of CCC include hepatocyte nuclear factor 1 beta (HNF1β) and Napsin A. In order to explore the utility of these markers in distinguishing between GAS and CCC, we stained 24 cases of GAS (19 cervical, 5 vaginal), 3 of cervical gastric-type adenocarcinoma in situ (gAIS) and 14 CCCs (13 cervical, 1 vaginal) with these antibodies. We found HNF1β expression in 21 of 23 cases of GAS (91.3%; there was no material available for staining in 1 case), 3/3 cases of gAIS (100%) and 10 of 14 (71.4%) CCCs. Napsin A was expressed in 4 of 24 (16.7%) cases of GAS, 0 of 3 (0%) gAIS, and 11 of 14 (78.6%) CCC. On the basis of these findings, Napsin A is of value in resolving diagnostic confusion between GAS and CCC, whereas HNF1β lacks specificity and its use in this setting is discouraged.
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http://dx.doi.org/10.1097/PGP.0000000000000529DOI Listing
May 2019

Primary Vaginal Gastric-type Adenocarcinoma and Vaginal Adenosis Exhibiting Gastric Differentiation: Report of a Series With Detailed Immunohistochemical Analysis.

Am J Surg Pathol 2018 07;42(7):958-970

Department of Pathology, Belfast Health and Social Care Trust, Belfast.

So-called gastric-type adenocarcinoma and related premalignant lesions have been characterized in the cervix, but similar lesions are not widely recognized in the vagina. We report a series of 11 vaginal glandular lesions exhibiting gastric differentiation, comprising 5 cases of adenocarcinoma and 6 of adenosis. All cases occurred in adults (aged 33 to 69) with no known history of diethylstilboestrol exposure. The vaginal adenocarcinomas exhibited morphologic features identical to gastric-type adenocarcinoma of the cervix, but 1 case additionally demonstrated basaloid and sarcomatoid components, which have not been previously reported in cervical gastric-type adenocarcinoma. Immunohistochemically, the adenocarcinomas were positive for MUC6 (4/5), PAX8 (3/5), CK7 (5/5), CK20 (1/5), CDX2 (5/5), CA19.9 (5/5), CEA (4/5), CA125 (5/5), and hepatocyte nuclear factor 1β (5/5). p16, estrogen receptor, and Napsin A were negative in all cases tested, whereas p53 exhibited mutation-type staining in 3/5 cases. In all 5 adenocarcinomas, a component of adenosis with benign or atypical nuclear features was identified; the adenosis displayed gastric morphology in 4 cases and tuboendometrial morphology in 1. The 6 cases of pure vaginal adenosis (without associated adenocarcinoma) all contained gastric-type mucinous glands together with tuboendometrial glands in 2 cases. There was focal intestinal differentiation with goblet cells in all 6 cases and neuroendocrine cells with eosinophilic granules in 3. Cytologic atypia was observed in 4/6 cases of pure vaginal adenosis. Immunohistochemically, the gastric-type adenosis (10 cases) was positive for MUC6 (10/10), estrogen receptor (5/10), PAX8 (8/10), CK7 (9/9), CK20 (2/9), CDX2 (5/9), CA19.9 (8/9), CEA (6/9), CA125 (6/9), hepatocyte nuclear factor 1β (10/10), and Napsin A (1/10). p53 exhibited wild-type immunoreactivity in all 10 cases, whereas p16 was negative in all cases tested. Scattered individual chromogranin-positive cells were present in all 5 cases of pure adenosis tested. Follow-up was available in 4 of the adenocarcinoma cases, with 3 patients dead of disease within 1 to 3 years and 1 patient alive with disease at 1 year. The morphologic and immunohistochemical findings in our study suggest a close relationship between vaginal gastric-type adenocarcinoma and adenosis exhibiting gastric differentiation. This probably represents a distinct pathway of vaginal gastric-type carcinogenesis analogous to that occurring in the cervix. We propose that gastric-type adenocarcinoma be recognized as a distinct histologic subtype of vaginal adenocarcinoma while vaginal adenosis of gastric-type represents a novel subtype of adenosis that requires further study to clarify its biological potential.
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http://dx.doi.org/10.1097/PAS.0000000000001068DOI Listing
July 2018

The developing spectrum of gastric-type cervical glandular lesions.

Pathology 2018 Feb 9;50(2):122-133. Epub 2017 Dec 9.

Department of Pathology, Belfast Health and Social Care Trust, Belfast, Northern Ireland, United Kingdom.

Adenocarcinoma of the cervix is less common than squamous cell carcinoma, although its relative prevalence is increasing. Oncogenic (high-risk) human papillomavirus (HPV) infection is implicated in the development of approximately 90% of all cervical adenocarcinomas. Of the remaining non-HPV associated tumours, the most frequent is gastric-type adenocarcinoma (GAS), which is recognised by the World Health Organization as a form of mucinous adenocarcinoma of the cervix. Minimal deviation adenocarcinoma (MDA) of mucinous type (adenoma malignum) is considered an extremely well differentiated variant of GAS and is encompassed within the category of GAS. The concept of gastric-type cervical glandular lesions has emerged over recent decades and our understanding of the full spectrum of benign, premalignant and malignant lesions is still evolving. Established benign lesions, which are rare, include simple gastric metaplasia and lobular endocervical glandular hyperplasia (LEGH) (complex gastric metaplasia). Postulated premalignant lesions comprise atypical LEGH and gastric-type adenocarcinoma in situ (gAIS); these are probably related lesions for which the umbrella term 'gAIS' has been proposed. The term 'gastric-type' derives from the morphological resemblance of the glandular epithelium to that seen in the stomach and pancreaticobiliary tree; intestinal metaplasia with goblet cells and neuroendocrine cells are present in some cases. A gastric immunophenotype has been demonstrated using markers of pyloric gland mucin, MUC6 and HIK1083. Uncommonly, gastric-type cervical glandular lesions involve multiple sites in the female genital tract and it may be problematic to discern whether these represent independent synchronous or metastatic lesions. There is also an association between gastric-type cervical lesions and Peutz-Jeghers syndrome. Awareness of the spectrum of gastric-type lesions is important, as the diagnostic features of both gAIS and GAS, particularly well differentiated examples, may be subtle, and p16 immunohistochemistry is usually negative. GAS has a much poorer prognosis than HPV-associated cervical adenocarcinoma, with propensity for presentation at advanced stage and wide dissemination to unusual sites such as the ovary, omentum and peritoneum. Although uncommon, GAS is likely to increase in relative prevalence with the introduction of HPV vaccination and precursor lesions will not be detected by primary HPV-based screening programs.
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http://dx.doi.org/10.1016/j.pathol.2017.09.009DOI Listing
February 2018

Human Papillomavirus-Associated Adenocarcinoma In Situ of the Vestibule.

J Low Genit Tract Dis 2017 10;21(4):e45-e47

1Department of Pathology, Box Hill Hospital, Eastern Health, Melbourne, Victoria, Australia; 2Hunter Centre for Gynaecological Cancer, John Hunter Hospital, New Lambton Heights, New South Wales, Australia; 3The Royal Women's Hospital and Murdoch Children's Research Institute, Parkville, Victoria, Australia; 4Department of Microbiology and Infectious Diseases Laboratory Services, Murdoch Childrens Research Institute, Parkville, Australia; and 5Anatomical Pathology, Pathology North, Hunter New England, New Lambton, New South Wales, Australia.

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http://dx.doi.org/10.1097/LGT.0000000000000347DOI Listing
October 2017

HPV-negative Gastric Type Adenocarcinoma In Situ of the Cervix: A Spectrum of Rare Lesions Exhibiting Gastric and Intestinal Differentiation.

Am J Surg Pathol 2017 Aug;41(8):1023-1033

*Department of Pathology, Box Hill Hospital, Melbourne, Vic. †Department of Histopathology, King Edward Memorial Hospital, Perth, WA, Australia ‡Department of Pathology, Brigham and Women's Hospital, Boston, MA §Department of Pathology, Belfast Health and Social Care Trust, Belfast, UK.

In recent years, a number of benign and malignant cervical glandular lesions exhibiting gastric differentiation have been described but premalignant gastric-type lesions have not been well characterized. We report a series of 9 cases of a rare form of cervical adenocarcinoma in situ (AIS) distinguished by gastric and sometimes intestinal differentiation and lack of association with human papillomavirus (HPV) infection. The lesions occurred in women aged 25 to 73 years (mean age 51 y). All cases were located at (or just proximal to) the cervical transformation zone and there was extension to the lower uterine segment in 3 cases, 2 of which also involved the endometrium. In all cases, the normal cervical glandular architecture was largely preserved but in 5 cases there was a mild degree of increased intraglandular architectural complexity. The glandular epithelium ranged from almost purely gastric in type (4 cases) to mixed gastric and intestinal (5 cases), with varying proportions of intermixed goblet cells. In contrast to the basophilic cytoplasm of normal endocervical glands, the gastric-type epithelium was typically predominantly composed of cells with eosinophilic or pale pink cytoplasm, but conspicuous foamy or clear cell cytoplasm was present in some cases. Nuclear atypia was present in all cases but was considered low-grade in 8. High-grade features such as marked nuclear pleomorphism and hyperchromasia were evident in only 1 case. Mitotic activity and apoptotic bodies were present but both were noted to be less frequent than in usual type (HPV-related) AIS. Immunohistochemically, there was usually positive staining with CK 7 (7/7 cases) and MUC 6 (7/8 cases) and some cases were positive with CK 20 (3/7), CDX2 (5/9), PAX 8 (5/9) and CEA (2/6). Estrogen receptor and progesterone receptor were usually negative, although Estrogen receptor was positive in 3 of 9 cases. p16 was negative or exhibited mosaic-type staining (nonblock staining) in all cases and there was mutation-type p53 staining in 2 of 9 cases. HPV molecular testing was negative in all 4 cases tested. We believe this unusual subtype of AIS, which we term "gastric-type AIS (gAIS)," represents a precursor to gastric-type adenocarcinoma of the cervix and suggest that gAIS and so-called "atypical lobular endocervical glandular hyperplasia" are related entities within a spectrum of premalignant gastric-type lesions for which we propose the umbrella term gAIS. The malignant potential and optimal management of gAIS are currently unknown but in one of our cases a gastric-type adenocarcinoma developed 6 years after removal of a cervical polyp which contained gAIS. The introduction of HPV vaccination will result in a relative increase in incidence of premalignant and malignant cervical glandular lesions exhibiting gastric differentiation and these will not be detected by HPV-based screening programs.
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http://dx.doi.org/10.1097/PAS.0000000000000855DOI Listing
August 2017

Seborrheic Keratosis-like Lesions of the Cervix and Vagina: Report of a New Entity Possibly Related to Low-risk Human Papillomavirus Infection.

Am J Surg Pathol 2017 Apr;41(4):517-524

*Department of Pathology, Box Hill Hospital, Eastern Health, Melbourne, Vic., Australia †Department of Pathology, Belfast Health and Social Care Trust, Belfast, UK.

We report a series of 7 unusual and morphologically distinct cervical or upper vaginal lesions in women aged 41 to 70 years. The lesions involved the cervix in 3 cases, the upper vagina in 2, the cervix and vagina in 1, and in 1 case the site of origin could not be determined. The lesions had a consistent morphologic appearance with a surface "plaque-like" or "stuck-on" configuration apparent in those cases where surrounding normal tissues were present. Broad coalescing solid sheets and interconnecting trabeculae of cytologically bland cells with a rather "basaloid" appearance emanated from the surface and there were scattered squamous eddies. Other features included peripheral palisading and a stroma containing hyalinized basement membrane-like material. Immunohistochemically, the lesions were diffusely positive with p63, CK5/6, and 34βE12 and focally positive with CK7, but largely negative with CK20, EMA, CEA, and BerEP4. p16 was negative or exhibited nonblock-type immunoreactivity and GATA3 was negative or weakly positive. Molecular testing detected human papillomavirus type 42 in 3 of 7 cases, with no virus detected in the remaining 4 cases. Rarely, similar cases have been reported previously as inverted transitional papilloma of the cervix or vagina, but based on the morphology and immunophenotype we do not feel these represent transitional lesions. We suggest the term seborrheic keratosis-like lesions to designate this new and rare entity, which may be associated with low-risk human papillomavirus infection. Limited follow-up in a small number of cases suggests that these lesions follow a benign clinical course.
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http://dx.doi.org/10.1097/PAS.0000000000000762DOI Listing
April 2017

A Detailed Immunohistochemical Analysis of a Large Series of Cervical and Vaginal Gastric-type Adenocarcinomas.

Am J Surg Pathol 2016 May;40(5):636-44

*Department of Pathology, Belfast Health and Social Care Trust, Belfast ‡Department of Pathology, UHCW NHS Trust, Coventry, UK †Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY §Department of Pathology, Jikei University School of Medicine, Tokyo, Japan ∥Department of Pathology, North Western State Medical University, St. Petersburg, Russia ¶Department of Pathology, Box Hill Hospital, Melbourne, Vic., Australia.

Adenocarcinomas exhibiting gastric differentiation represent a recently described and uncommon subtype of non-human papillomavirus (HPV)-related cervical adenocarcinoma. They comprise a spectrum from a well-differentiated variant (adenoma malignum/mucinous variant of minimal deviation adenocarcinoma) to a more poorly differentiated overtly malignant form, generally referred to as gastric-type adenocarcinoma. Rarely, such tumors have also been described as primary vaginal neoplasms. Gastric-type adenocarcinomas exhibit considerable morphologic overlap with adenocarcinomas originating outside the female genital tract, especially mucinous adenocarcinomas arising in the pancreas and biliary tract. Moreover, they often metastasize to unusual sites, such as the ovary and peritoneum/omentum, where they can be mistaken for metastatic adenocarcinomas from other, nongynecologic sites. There is little information regarding the immunophenotype of gastric-type adenocarcinomas, and knowledge of this is important to aid in the distinction from other adenocarcinomas. In this study, we undertook a detailed immunohistochemical analysis of a large series of cervical (n=45) and vaginal (n=2) gastric-type adenocarcinomas. Markers included were cytokeratin (CK)7, CK20, CDX2, carcinoembryonic antigen, CA125, CA19.9, p16, estrogen receptor, progesterone receptor, MUC6, PAX8, PAX2, p53, hepatocyte nuclear factor 1 beta, carbonic anhydrase IX, human epidermal receptor 2 (HER2), and mismatch repair (MMR) proteins. All markers were classified as negative, focal (<50% of tumor cells positive), or diffuse (≥50% tumor cells positive) except for p53 (classified as "wild-type" or "mutation-type"), HER2 (scored using the College of American Pathologists guidelines for gastric carcinomas), and MMR proteins (categorized as retained or lost). There was positive staining with CK7 (47/47-45 diffuse, 2 focal), MUC6 (17/21-6 diffuse, 11 focal), carcinoembryonic antigen (25/31-12 diffuse, 13 focal), carbonic anhydrase IX (20/24-8 diffuse, 12 focal), PAX8 (32/47-20 diffuse, 12 focal), CA125 (36/45-5 diffuse, 31 focal), CA19.9 (11/11-8 diffuse, 3 focal), hepatocyte nuclear factor 1 beta (13/14-12 diffuse, 1 focal), CDX2 (24/47-4 diffuse, 20 focal), CK20 (23/47-6 diffuse, 17 focal), and p16 (18/47-4 diffuse, 14 focal). Most cases were negative with estrogen receptor (29/31), progesterone receptor (10/11), PAX2 (18/19), and HER2 (25/26). p53 showed "wild-type" and "mutation-type" staining in 27 of 46 and 19 of 46 cases, respectively. MMR protein expression was retained in 19 of 20 cases with loss of MSH6 staining in 1 patient with Lynch syndrome. Molecular studies for HPV were undertaken in 2 tumors, which exhibited diffuse "block-type" immunoreactivity with p16, and both were negative. This is the first detailed immunohistochemical study of a large series of gastric-type adenocarcinomas of the lower female genital tract. Our results indicate immunophenotypic overlap with pancreaticobiliary adenocarcinomas but suggest that PAX8 immunoreactivity may be especially useful in distinguishing gastric-type adenocarcinomas from pancreaticobiliary and other nongynecologic adenocarcinomas, which are usually negative. Diffuse "block-type" p16 immunoreactivity in a cervical adenocarcinoma is not necessarily indicative of a high-risk HPV-associated tumor.
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http://dx.doi.org/10.1097/PAS.0000000000000578DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5564425PMC
May 2016

A case of HPV-negative intestinal-type endocervical adenocarcinoma in situ with coexisting multifocal intestinal and gastric metaplasia.

Am J Surg Pathol 2014 Feb;38(2):289-91

*Department of Pathology Box Hill Hospital, Eastern Health Melbourne, Vic., Australia †Department of Pathology, Belfast Health and Social Care Trust, Belfast, Northern Ireland, UK.

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http://dx.doi.org/10.1097/PAS.0000000000000139DOI Listing
February 2014

Primary vaginal mucinous adenocarcinoma of gastric type arising in adenosis: a report of 2 cases, 1 associated with uterus didelphys.

Int J Gynecol Pathol 2012 Mar;31(2):184-191

Department of Pathology, Box Hill Hospital, Eastern Health, Melbourne, Victoria, Australia.

We report 2 cases of primary vaginal mucinous adenocarcinoma arising in adenosis in nondiethylstilbestrol-exposed women, 1 with uterus didelphys. Both tumors exhibited morphologic and immunohistochemical features (MUC6 and/or HIK 1083 positivity) identical to the recently described cervical gastric-type adenocarcinoma, a subtype of mucinous adenocarcinoma that is non-human papillomavirus related and possibly related to adenoma malignum. Both neoplasms were intensely p53 positive, suggesting that TP53 mutation may be implicated in their development. We believe that the vaginal tumors arose from adenosis through atypical adenosis, as benign and atypical glands were present at the periphery of the neoplasms. In reporting these cases, we discuss atypical adenosis and other types of non-diethylstilbestrol-associated vaginal adenocarcinomas. At least 9 other examples of primary vaginal, or more uncommonly cervical, adenocarcinomas arising in non-diethylstilbestrol-exposed women with congenital genitourinary malformations have been reported, suggesting a probable causal association between congenital malformation, vaginal adenosis, and vaginal adenocarcinoma.
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http://dx.doi.org/10.1097/PGP.0b013e31822c8036DOI Listing
March 2012
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