To date, the impact of the human papillomavirus (HPV) vaccine on invasive cervical cancers in the United States has not been documented due, in part, to the time needed for cancer to develop and to recent changes to cervical cancer screening guidelines and recommendations, which complicate data interpretation.

Recent trends of cervical cancer incidence by histology and age in the United States (U.S.) have not been reported. We examined contemporary trends in cervical squamous cell carcinoma (SCC) and adenocarcinoma (AC) incidence rates in the U.S. by age group, race/ethnicity, and stage at diagnosis after accounting for hysterectomy. Incidence data (1999-2015) were obtained from the U.S. Cancer Statistics Incidence Analytic Database. Hysterectomy prevalence was estimated using National Health Interview Survey data (2000-2015). Overall SCC incidence rates continued to decrease in all racial/ethnic groups except among non-Hispanic whites in whom rates stabilized in the 2010s, largely driven by stable trends in ages <50 years and a slower pace of decrease in ages 50-59 years. After a stable trend between 1999 and 2002, AC incidence rates among non-Hispanic whites rose during 2002-2015 (1.3% per year), mostly due to increases in ages 40-49 (4.4% annually since 2004) and 50-59 years (5.5% annually since 2011). Overall AC incidence rates during 1999-2015 decreased in blacks and Hispanics but were stable in Asian/Pacific Islanders; in all these race/ethnicities, rates were generally stable in ages <50 years but decreasing in older ages. Rates of distant stage cervical SCC and AC among non-Hispanic whites increased in several age groups but were generally stable in non-whites. Increasing or stabilized incidence trends for AC and attenuation of earlier declines for SCC in several subpopulations underscore the importance of intensifying efforts to reverse the increasing trends and further reduce the burden of cervical cancer in the U.S.Copyright © 2019 Elsevier Inc. All rights reserved.

We sought to classify endocervical adenocarcinomas (ECAs) based on morphologic features linked to etiology (ie, human papillomavirus [HPV] infection), unlike the World Health Organization 2014 classification. The International Endocervical Adenocarcinoma Criteria and Classification (IECC criteria), described herein, distinguishes between human papillomavirus-associated adenocarcinoma (HPVA), recognized by the presence of luminal mitoses and apoptosis seen at scanning magnification, and no or limited HPVA features (nonhuman papillomavirus-associated adenocarcinoma [NHPVA]). HPVAs were then subcategorized based on cytoplasmic features (mostly to provide continuity with preexisting classification schemes), whereas NHPVAs were subclassified based on established criteria (ie, gastric-type, clear cell, etc.). Complete slide sets from 409 cases were collected from 7 institutions worldwide. Tissue microarrays representing 297 cases were constructed; immunohistochemistry (p16, p53, vimentin, progesterone receptor) and chromogenic in situ hybridization using an RNA-based probe set that recognizes 18 varieties of high-risk HPV were performed to validate IECC diagnoses. The 5 most common IECC diagnoses were usual-type (HPVA) (73% of cohort), gastric-type (NHPVA) (10%), mucinous adenocarcinoma of HPVA type, including intestinal, mucinous not otherwise specified, signet-ring, and invasive stratified mucin-producing carcinoma categories (9%), clear cell carcinoma (NHPVA) (3%) and adenocarcinoma, not otherwise specified (2%). Only 3 endometrioid carcinomas were recognized and all were NHPVA. When excluding cases thought to have suboptimal tissue processing, 90% and 95% of usual-type IECC cases overexpressed p16 and were HPV, whereas 37% and 3% of NHPVAs were p16 and HPV, respectively. The 1 HPV gastric-type carcinoma was found to have hybrid HPVA/NHPVA features on secondary review. NHPVA tumors were larger and occurred in significantly older patients, compared with HPVA tumors (P<0.001). The high-risk HPV chromogenic in situ hybridization probe set had superior sensitivity, specificity, and positive and negative predictive values (0.955, 0.968, 0.992, 0.833, respectively) compared with p16 immunohistochemistry (0.872, 0.632, 0.907, 0.545, respectively) to identify HPV-related usual carcinoma and mucinous carcinoma. IECC reliably segregates ECAs into HPVA and NHPVA types using morphology alone. This study confirms that usual-type ECAs are the most common type worldwide and that mucinous carcinomas comprise a mixture of HPVA and NHPVA, with gastric-type carcinoma being the major NHPVA type. Endometrioid and serous carcinomas of the endocervix are extraordinarily rare. Should clinical outcomes and genomic studies continue to support these findings, we recommend replacement of the World Health Organization 2014 criteria with the IECC 2017.

The revised World Health Organization classification of cervical cancer divides adenocarcinomas into human papillomavirus-associated (HPVa) and -independent (HPVi) types; the HPVi type is represented by the gastric type. The treatment outcomes of locally advanced adenocarcinoma (LaAC), based on this classification, are understudied. We investigated the outcomes of patients with HPVa and HPVi LaACs. Data for all consecutive patients with stage IB3 to IIIC1 adenocarcinoma who received treatment at 12 institutions throughout Japan between 2004 and 2009 were retrieved to analyze progression-free and overall survival. Central pathological review classified 103 and 48 patients as having HPVa and HPVi tumors, respectively. Usual- (84%) and gastric- (90%) type adenocarcinomas were the most frequent subtypes. Surgery was the primary treatment strategy for most patients. Progression-free and overall survival of patients with HPVi were worse than those of patients with HPVa (p = 0.009 and 0.032, respectively). Subgroup analysis by stage showed that progression-free survival was significantly different for stage IIB. The current surgical treatment strategy for LaACs is less effective for HPVi tumors than for HPVa tumors, especially those in stage IIB.

Among cervical adenocarcinomas, well-differentiated gastric adenocarcinoma of the uterine cervix (WD-GAS), previously termed adenoma malignum (minimal deviation adenocarcinoma) is not well understood. Because of its rarity and difficulty in diagnosis, there is no standard care for WD-GAS. Thus, we conducted the first multicenter retrospective study on WD-GAS to clarify prognostic factors for long-term survival and recurrence.Patients diagnosed with WD-GAS at eight hospitals participated in this multi-center study. Overall survival (OS) and recurrence-free survival (RFS) were calculated with the Kaplan-Meier method. Additionally, OS between the early and advanced FIGO stage groups were compared with the log-rank test. Cox regression analysis was conducted to identify significant factors associated with recurrence-free survival (RFS).A total of 73 patients from eight hospitals in South Korea were included in the analysis. The median follow-up period was 44.8 months, and all patients underwent curative surgical intervention as the primary treatment. Recurrence was observed in 17 patients (23.3%). Ten patients had locoregional recurrence, four patients had distant metastasis, and three patients presented with both locoregional recurrence and distant metastasis. The Cox regression analysis identified several statistically significant factors associated with RFS, including vaginal invasion (VI), parametrial invasion (PMI), resection margin (RM), and nodal and lymphovascular invasion (LVI). When considering these five factors together, patients without any of the factors exhibited recurrence-free survival (RFS) of 97.0% at three years and those with more than one of these factors had a 3-year RFS of 65.4% (P < 0.001).WD-GAS showed relatively high locoregional recurrence rate. Positive PMI, VI, RM, nodal involvement, and LVI were associated with a significant increase in recurrence or distant metastasis rates.Copyright © 2024. Published by Elsevier Inc.

Endocervical adenocarcinoma is divided into human papillomavirus (HPV)-associated (HPVA) and HPV-independent (HPVI) in the 5th edition of the World Health Organization (WHO) tumor classification launched in 2020. However, the validity of the morphologic criteria used for biopsy specimens in real-world practice remains undetermined.

Background/Objectives: In order to develop a comprehensive understanding of gastric-type endocervical adenocarcinoma (GEA), an increasingly prevalent HPV-independent cervical cancer, we summarized clinicopathological information and performed prognostic analysis. Methods: A total of 182 patients diagnosed with GEA at our center during the period 2014–2025 were included in this study. Nineteen GEA cases, 6 HPV-independent non-GEA cases, 59 HPV-associated usual endocervical adenocarcinoma cases, and 66 squamous cell carcinoma cases from online database were also included. Results: Vaginal bleeding (39.56%) and watery discharge (35.16%) were the most common symptoms. As many as 21.43% of patients had no specific complaints, and 80% of GEA showed no distinct mass through gynecological examination. A total of 64% of GEA were stage IIB–IV at diagnosis, with a 5-year survival of 41% versus 85% for stage I–IIA (p < 0.05). The rate of lymphovascular space invasion (LVSI), lymph node metastasis, and ovarian metastasis were 49.64%, 42.00%, and 29.29%, respectively. The 5-year survival and recurrence rates after primary therapy were 57% and 23%, respectively. For GEA treatment, surgery might be associated with improved overall survival for the population at stage III–IV. Survival analysis identified deep infiltration depth (≥2/3), a maximum diameter of the tumor (MDOT) of ≥3 cm, and ovary metastasis as potential indicators of worse OS and PFS for whole patients. Additionally, ovary metastasis indicated poor PFS and OS for stage I–II. Genomic information TP53 mutation, PTEN deletion and STK11 mutation might be the most prevalent genomic alterations. Conclusions: These findings indicated GEA as an aggressive cervical cancer, with high rate of lymph node metastasis, high recurrence rate and short 5-year survival. Ovary metastasis reflected advanced disease burden and surgery might be associated with improved survival in advanced stage. For genomic information, GEA showed genetic heterogeneity and a low level of genomic instability.

Endocervical-type mucinous adenocarcinoma (ECA) of the uterine cervix is defined as a tumor composed of cells resembling those of the endocervical glands, but recent studies have demonstrated that a minority of ECAs displays a gastric immunophenotype. The aim of this study was to assess the significance of the gastric phenotype. Fifty-three cases of mucinous adenocarcinoma of the uterine cervix (37 FIGO stage IB, 4 stage IIA, and 12 stage IIB) were reviewed and reevaluated using a newly established morphologic criteria for distinguishing gastric type adenocarcinoma, which was defined as a tumor showing clear and/or pale eosinophilic and voluminous cytoplasm, with distinct cell borders. The results were correlated with gastric immunophenotype, determined by HIK1083 and MUC6 immunostaining, and patient outcome. Following the current World Health Organization scheme (2003), 47 tumors (89%) were classified as ECA, 1 (2%) as intestinal type, 1 (2%) as mixed endocervical and intestinal type, and 4 (8%) as minimal deviation adenocarcinoma. Twelve of 47 (26%) ECAs and all 4 minimal deviation adenocarcinomas, reclassified as gastric type using the novel criteria, were frequently positive for HIK1083 with a rate of 75% (12/16), whereas only 11% (4/37) of nongastric tumors were positive. There was no significant difference in MUC6 reactivity between gastric and nongastric type tumors (31%, 5/16 vs. 16%, 6/37; P=0.4). Patients with gastric-type adenocarcinomas had a significantly decreased 5-year disease-specific survival rate (30 vs. 77%; P<0.0001), and the gastric type morphology was related to a significant risk for disease recurrence compared with the nongastric type (P=0.001; HR, 4.5; 95% confidence interval, 1.42-14.2). HIK1083-positivity was also related to decreased 5-year disease-specific survival rate (38% vs. 74%; P<0.005). Mucinous adenocarcinoma of the uterine cervix with gastric immunophenotype can be a distinct morphologic variant showing an aggressive clinical course.

Gastric-type endocervical adenocarcinoma (GEA) is a rare form of cervical cancer not associated with human papilloma virus (HPV) infection. We summarize our experience with GEA at a large cancer center.Clinical and demographic information on all patients diagnosed with GEA between June 1, 2002 and July 1, 2019 was obtained retrospectively from clinical charts. Kaplan-Meier survival analysis was performed to describe progression-free survival (PFS) and overall survival (OS). Tumors from a subset of patients underwent next generation sequencing (NGS) analysis.A total of 70 women with GEA were identified, including 43 who received initial treatment at our institution: of these 4 (9%) underwent surgery alone, 15 (35%) underwent surgery followed by adjuvant therapy, 10 (23%) were treated with definitive concurrent chemoradiation (CCRT), 7 (16%) with chemotherapy alone, and 3 (7%) with neoadjuvant CCRT and hysterectomy with or without chemotherapy. One-third (n = 14) of patients experienced disease progression, of whom 86% (n = 12) had prior CCRT. The median PFS and OS for patients with stage I GEA were 107 months (95% CI 14.8-199.2 months) and 111 months (95% CI 17-205.1 months) respectively, compared to 17 months (95% CI 5.6-28.4 months) and 33 months (95% CI 28.2-37.8 months) for patients with stages II-IV, respectively. On NGS, 4 patients (14%) had ERBB2 alterations, including 2 patients who received trastuzumab.GEA is an aggressive form of cervical cancer with poor PFS and OS when diagnosed at stage II or later. Further investigation is needed to identify the optimal management approach for this rare subtype.Copyright © 2022 Elsevier Inc. All rights reserved.

Microbial community dynamics have been involved in numerous diseases, including cancer. The diversity of intertumoral microbiota in human papillomavirus independent endocervical adenocarcinoma (HPVI ECA) is not well-characterized.

A variety of benign and malignant endocervical glandular lesions exhibiting gastric differentiation has been described in the past decade that has resulted in the concept of an important category of cervical adenocarcinoma which is unrelated to human papillomavirus (HPV). Both minimal deviation adenocarcinoma (MDA), also known as adenoma malignum, and the benign lesion lobular endocervical glandular hyperplasia (LEGH), have been known for some time to exhibit a gastric phenotype and immunophenotype (HIK1083 and/or MUC6 positive). Accumulated evidence suggests that a subset of LEGH (atypical LEGH) exhibits a degree of cytologic and/or architectural atypia which, in some cases, may be associated with and be a precursor of adenocarcinomas exhibiting gastric differentiation, including MDA. Gastric-type adenocarcinoma (GAS), a recently described subtype of cervical adenocarcinoma, is an emerging clinicopathologic entity. These neoplasms exhibit a spectrum of differentiation, including MDA as its very well-differentiated form, are unrelated to HPV, and exhibit aggressive clinical behavior. It is proposed that a LEGH-GAS sequence exists and, from a practical point of view, the development of optimal biomarkers is awaited to assist in early detection of GAS and atypical LEGH, as current HPV-targeted screening generally does not detect these lesions and strategies employing HPV vaccination will not prevent their occurrence. Pathologists should be familiar with the morphologic spectrum of these benign, premalignant, and malignant cervical glandular lesions exhibiting gastric differentiation. They are occasionally associated with Peutz-Jeghers syndrome or are a component of "synchronous mucinous metaplasia and neoplasia of the female genital tract."

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.

Lobular endocervical glandular hyperplasia (LEGH) is a multicystic proliferative disorder of the uterine cervix. The aim of this review was to clarify the current understanding of this unique tumor.

Although an increased cancer risk in Peutz-Jeghers syndrome is established, data on the spectrum of tumors associated with the disease and the influence of germ-line STK11/LKB1 (serine/threonine kinase) mutation status are limited.We analyzed the incidence of cancer in 419 individuals with Peutz-Jeghers syndrome, and 297 had documented STK11/LKB1 mutations.Ninety-six cancers were found among individuals with Peutz-Jeghers syndrome. The risk for developing cancer at ages 20, 30, 40, 50, 60, and 70 years was 2%, 5%, 17%, 31%, 60%, and 85%, respectively. The most common cancers represented in this analysis were gastrointestinal in origin, gastroesophageal, small bowel, colorectal, and pancreatic, and the risk for these cancers at ages 30, 40, 50, and 60 years was 1%, 9%, 15%, and 33%, respectively. In women with Peutz-Jeghers syndrome, the risk of breast cancer was substantially increased, being 8% and 31% at ages 40 and 60 years, respectively. Kaplan-Meier analysis showed that cancer risks were similar in Peutz-Jeghers syndrome patients with identified STK11/LKB1 mutations and those with no detectable mutation (log-rank test of difference chi2 = 0.62; 1 df; P = 0.43). Furthermore, the type or site of STK11/LKB1 mutation did not significantly influence cancer risk.The results from our study provide quantitative information on the spectrum of cancers and risks of specific cancer types associated with Peutz-Jeghers syndrome.

To perform a systematic review of gastric-type adenocarcinoma of the cervix and lobular endocervical glandular hyperplasia (a possible precursor lesion) in Peutz-Jeghers syndrome, and to analyze data from the literature, along with our institutional experience, to determine recommendations for screening and detection.A comprehensive literature searc and retrospective search of pathology records at our institutio were conducted. Articles were screened by two independent reviewers. Case reports/series on lobular endocervical glandular hyperplasia/gastric-type adenocarcinoma of the cervix in Peutz-Jeghers syndrome were included. Demographic, clinical, and radiologic information was collected.A total of 1564 publications were reviewed; 38 met the inclusion criteria. Forty-nine were included in the analysis (43 from the literature, 6 from our institution). Forty-three reported on gastric-type adenocarcinoma alone, 4 on lobular endocervical glandular hyperplasia alone, and 2 on concurrent lobular endocervical glandular hyperplasia/gastric-type adenocarcinoma. Median age at diagnosis was 17 (range, 4-52) for patients with lobular endocervical glandular hyperplasia alone and 35 (range, 15-72) for those with gastric-type adenocarcinoma. The most common presenting symptoms were abdominal/pelvic pain and vaginal bleeding/discharge. Imaging was reported for 27 patients; 24 (89%) had abnormal cervical features. Papanicolaou (Pap) smear prior to diagnosis was reported for 12 patients; 6 (50%) had normal cytology, 4 (33%) atypical glandular cells, and 2 (17%) atypical cells not otherwise specified. Patients with gastric-type adenocarcinoma (n=45) were treated with surgery alone (n=16), surgery/chemotherapy/radiation (n=11), surgery/chemotherapy (n=9), surgery/radiation (n=5), or radiation/chemotherapy (n=4). Twelve (27%) of 45 patients recurred; median progression-free survival was 10 months (range, 1-148). Twenty patients (44%) died; median overall survival was 26 months (range, 2-156). Thirteen patients (27%) were alive with no evidence of disease.Gastric-type adenocarcinoma in Peutz-Jeghers syndrome is associated with poor outcomes and short progression-free and overall survival. Screening recommendations, including pathognomonic symptom review and physical examination, with a low threshold for imaging and biopsy, may detect precursor lesions and early-stage gastric-type adenocarcinoma, leading to better outcomes in this high-risk population.CRD42019118151.© IGCS and ESGO 2022. No commercial re-use. See rights and permissions. Published by BMJ.

To compare and explore the characteristics of squamous cell carcinoma (SCC), adenocarcinoma (AC) and adenosquamous carcinoma (ASC), usual-type endocervical adenocarcinoma (UEA) and gastric adenocarcinoma (GAC) of cervix.A total of 728 cervical cancers (254 cases of AC, 252 cases of ASC, and 222 cases of SCC) confirmed by histopathology were retrospectively reviewed. Among AC, 119 UEA and 47 GAC were included. Clinical baseline data and tumor morphological features on MRI (including tumor location, shape, diameter and volume, margin, growth pattern, presence of fluid component or cyst, heterogenous and peritumoral enhancement) of all cases were collected and analyzed. The signal intensity (SI) of tumor and gluteus maximus muscle were measured and their ratios (SIR) were calculated based on T1-weighted imaging (T1WI), T2-weighted imaging (T2WI), diffusion-weighted imaging (DWI), apparent diffusion coefficient (ADC) and contrast-enhanced T1WI at arterial and delay phases (A/DCE-T1WI). These clinical and MRI features were compared between SCC, AC and ASC, UEA and GAC, and the specific ones of each subtype were identified.There was a significant difference in SCC-Ag, CA-199, CEA, ADC value, SIR-DWI, presence of intratumor cyst and peritumoral enhancement between AC and ASC; in patient age, menopausal status, International Federation of Gynecology and Obstetrics (FIGO) stage, SCC-Ag, CA-125, CA-199, CEA, tumor shape, growth pattern, margin, presence of intratumor fluid component and cyst, tumor diameter and volume, ADC value, SIR-T1WI, SIR-T2WI, and SIR-DWI between SCC and AC, as well as SCC and ASC. Also, there was a significant difference in deep stromal invasion (DSI), peritumoral and heterogenous enhancement between SCC and AC, and in SIR-ACE-T1WI between SCC and ASC. There was a significant difference in reproductive history, menopausal status, FIGO stage, CA-199, DSI, lymph node metastasis (LNM), parametrial invasion (PMI), tumor location, shape, margin, growth pattern, presence of fluid component and cyst, tumor diameter and volume, SIR-T1WI, SIR-DWI, and heterogenous enhancement between GAC and UEA.The clinical and MRI features with significant differences among SCC, AC and ASC, and between UEA and GAC, can help to identify each subtype of cervical cancer.Copyright © 2024. Published by Elsevier Inc.

To quantitatively differentiate MRI localization of gastric-type adenocarcinoma (GAS) and lobular endocervical glandular hyperplasia (LEGH) from other benign cystic lesions (OBC).We retrospectively reviewed T1-weighted (T1WI) and T2-weighted images (T2WI) and measured the lesion volume, the ratio of cervical canal position at the maximum cross-section (deviation ratio), the ratio of the lesion's centre within the craniocaudal length (longitudinal location ratio), distance from the internal and external os, maximum cyst diameter, and signal intensities of the cyst content on T1WI and T2WI (T1 and T2 ratios). These parameters were compared between GAS or LEGH and OBC, where OBC was clinically suspected of LEGH.Seventeen patients with GAS, 18 with LEGH (52 ± 11 years), and 42 with OBC (45 ± 10 years) were included. GAS/LEGH were larger in volume (29.25/15.24 cm3, P < .001), and had a greater deviation ratio (0.82/0.84, P < .001), shorter distance to the internal and external os (3.4/3.6 mm, P = .040, and 3.3/3.3 mm, P = .003, respectively), and a lower T1 ratio (1.08/0.91, P < .001). The area under the curve (AUC) of these parameters using their respective optimal cut-off values was 0.818, 0.756, 0.629, 0.711, and 0.731, respectively. When 3 or more positive criteria were considered, the AUC increased to 0.896.Compared with OBC, GAS/LEGH displayed a larger volume, cervical canal deviation, proximity to the internal and external os, and a lower T1 ratio of cyst content.Considering both the lesion and its relationship to the cervical canal is imperative for differentiating between the conditions.© The Author(s) 2025. Published by Oxford University Press on behalf of the British Institute of Radiology.

The preoperative diagnosis and management of Peutz-Jeghers syndrome (PJS) patients with cervical lesions remain problematic. This study analysed the associations between pathological types of cervical lesions in PJS patients and their MRI features. A total of 34 PJS patients were included and two experienced radiologists reviewed the MRIs independently. Based on the pathological diagnosis, the patients were categorized into four groups: normal (n  =  4), lobular endocervical glandular hyperplasia (LEGH, n  =  11), atypical LEGH (aLEGH, n  =  8), and gastric-type endocervical adenocarcinoma (G-EAC, n  =  11). By observing the MRI features, we found statistically significant differences in the extent of lesions (P  = 0 .001), distribution of microcysts (P  = 0 .001), proportion of microcysts (P  <  0.001) and endometrial involvement (P  = 0.019) among the four groups. Notably, solid components and disrupted cervical stromal rings were found only in the aLEGH and G-EAC groups (P  < 0.001).  Consequently, we created a novel grading system based on the aforementioned MRI features to align with the potential malignancy of cervical lesions in PJS patients. This system enables patients to receive timely and appropriate treatment recommendations while facilitating collaboration between radiologists and physicians.© 2024. The Author(s).

To investigate the clinical practices of diagnosing multicystic cervical lesions as a means to develop a more appropriate diagnostic algorithm for gastric-type adenocarcinoma (GAS) and its precursors.

Objective: To identify distinctive 18F-FDG positron emission tomography (PET)/computer tomography (CT) features of gastric-type endocervical adenocarcinoma (GAS) that differentiate it from squamous cell carcinoma (SCC) and usual-type endocervical adenocarcinoma (UEA), as well as to correlate these findings with pathological characteristics. Methods: Patients treated between December 2018 and December 2024 were retrospectively reviewed. The study included 12 GAS, 48 SCC, and 30 UEA cases. Evaluated parameters included tumor morphology, cystic components, uterine cavity fluid, N/M staging, tumor diameter, the cervical lesion maximum standardized uptake value (SUVmax), and the tumor-to-liver maximum standardized uptake ratio (T/L SUVmax). Results: GAS predominantly exhibited diffuse infiltrative growth (11/12), in contrast to mass-like growth observed in SCC (37/48) and UEA (24/30) (both p < 0.001). Cystic components, uterine cavity fluid, and peritoneal metastasis occurred significantly more frequently in GAS (12/12, 11/12, 5/12, respectively) compared to SCC and UEA (all p < 0.001). Elevated CA19-9 levels were more common in GAS (9/12) compared with SCC (p < 0.001). Tumor diameter did not differ significantly among the groups (p > 0.05). SUVmax and T/L SUVmax values were significantly lower in GAS (7.5 ± 3.8 and 2.5 ± 1.6, respectively) than in UEA (19.1 ± 11.4 and 5.7 ± 3.4) and SCC (17.4 ± 6.7 and 5.5 ± 2.6) (all p < 0.001). Conclusion: The clinical characteristics of GAS include infiltrative tumor growth, fluid accumulation in the uterine cavity, frequent formation of microcystic or macrocystic components, peritoneal metastasis, and elevated CA19-9 levels. In this cohort, SUVmax and T/L SUVmax values in GAS were significantly lower than those observed in SCC and UEA.

Gastric-type endocervical adenocarcinoma (GAS) is a recently described diagnostic entity originally characterized as a tumor with (1) voluminous cytoplasm that is (2) clear or pale eosinophilic, and (3) cells showing distinct cell borders. Since the initial tumor description there has been accumulating experience that the neoplasm, in addition to classic features, may show a wide spectrum of morphologic appearances. This paper describes and illustrates cases of GAS with focal or diffuse findings that include: densely eosinophilic cytoplasm, foamy cytoplasm, goblet cells, glands with elongated, stratified nuclei, glands with small cuboidal cells, glands with flattened cells, papillary growth, single cell infiltration and infiltration with microcystic elongated and fragmented pattern. All these patterns may bring up a differential diagnosis with other cervical malignancies such as usual, intestinal, endometrioid, clear cell, serous, and mesonephric adenocarcinoma. The paper describes the patterns of immunostaining of respective lesions that may aid in the diagnostic process and summarizes the main points of the differential diagnosis. GAS is associated with somatic and germline STK11 mutations and TP53 mutations but is invariably negative for human papilloma virus when tumor only is tested. It shows variation in incidence between countries. Awareness of the spectrum of morphologic appearances in GAS is important for accurate and confident diagnosis. Correct identification of GAS is important due to its propensity for ovarian and other distant metastases, markedly worse prognosis as compared with usual endocervical adenocarcinoma, and its relative resistance to chemotherapy.

Claudin‐18 (CLDN18) is both a marker for the gastric phenotype and a therapeutic target. However, little is known about its immunoexpression in endocervical adenocarcinomas (ECAs), particularly as detected using the clone 43‐14A antibody, or about the gene expression of its isoforms in ECAs.

Endometrial gastric (gastrointestinal)-type mucinous adenocarcinoma (EmGA) is rare and was introduced as a new entity in the latest World Health Organization (WHO) classification of female genital tumors. Herein, we report a detailed clinicopathologic, immunohistochemical, and molecular study of 27 EmGA, the largest published series to date. The cohort consisted of 27 patients (median age 69 y; range 42 to 87 years). Histologically all cases showed gastric/gastrointestinal differentiation with foamy apical cytoplasm with distinct cell borders (n=21), goblet cells (n=9), signet ring cells (n=4), and Paneth cells (n=1). Using FIGO grading, 5 were grade 1, 14 grade 2, and 8 grade 3. Tumors were positive for MUC6 (10/21), CK7 (22/24), CK20 (16/24), CDX2 (24/26), and Claudin 18 (9/12). In all, 12/27 exhibited aberrant p53 expression and 3/26 showed MLH1 and PMS2 loss, including 2 with confirmed MLH1 gene promoter methylation. Next-generation sequencing showed pathogenic variants in TP53 (13/20), KRAS (7/20), PIK3CA (5/20), BRCA2 (4/20), SMAD4 (3/20), and POLE (1/20). Using TCGA classification (based on cases with available molecular results), 1/20 was POLE mutated, 2/20 were mismatch repair deficient (MMRd), 4/20 were no specific molecular profile (NSMP), and 13/20 were TP53 abnormal. FIGO stage (2009 staging system) ranged from IA to IVB. Outcome data (21 patients; follow-up of 2 to 77 mo) showed that 2 patients died of disease at 14 and 46 months after diagnosis, 1 patient died from other causes at 28 months, 8 were alive with disease, and 10 were alive with no evidence of disease. Like the cervical counterpart, primary EmGA has a distinctive morphologic appearance, harbors frequent TP53 mutations, and can be associated with adverse outcomes despite low-grade morphology and/or low-stage at presentation. They may be represented in all 4 TCGA molecular groups.Copyright © 2025 Wolters Kluwer Health, Inc. All rights reserved.

Gastric‐type endocervical adenocarcinoma (EA) is characterised by aggressive behaviour and pathogenesis independent of human papillomavirus infection. Because of its morphology and frequent mutation‐pattern expression of p53, gastric‐type EA may be confused with several types of endometrial carcinoma, particularly in biopsy and curettage specimens. HIK1083 and MUC6 are immunohistochemical markers used to support a diagnosis of gastric‐type EA; however, the rates of expression of these markers in endometrial tumours are largely unknown. We therefore aimed to assess the expression of HIK1083 and MUC6 in a cohort of different types of endometrial carcinoma.

HIK1083 and trefoil factor 2 (TFF2) are known to be expressed in gastric-type carcinoma (GAS), but they do not reliably mark all GASs, and focal expression can be missed in biopsy specimens. We aimed to investigate whether claudin-18 and alpha-methylacyl-CoA racemase (AMACR) could be surrogate markers to separate GAS from other types of endocervical adenocarcinoma (ECA) and to compare their usefulness with that of HIK1083 and TFF2. Claudin-18 and AMACR immunohistochemistry was performed, and the results were compared with that of TFF2 and HIK1083, using whole sections of 75 ECAs (22 GASs and 53 non-GASs) and 179 ECAs with tissue microarrays (TMAs). TMAs were built to simulate the assessment of immunohistochemical stains in small biopsies. Any membranous (claudin-18) or cytoplasmic/membranous (AMACR, TFF2, HIK1083) staining of >5% of tumor cells was considered positive. Of 75 ECAs with whole sections, claudin-18 was significantly more frequently expressed in GASs (21/22) compared with non-GASs (8/53) (P<0.01). In ECAs with TMAs, claudin-18 expression was significantly frequent in GASs (15/23, 65.2%) than in non-GASs (3/152, 2.0%; all usual-type) (P<0.01). All claudin-18-positive GASs showed intense staining except 1 case. Claudin-18 shared the same degree of sensitivity and specificity with HIK1083 and TFF2. Three clear cell carcinomas were positive for claudin-18, but none showed intense staining. AMACR was expressed in a subset of ECAs and showed no impact in distinguishing between GAS and other ECAs. Our results suggest that claudin-18 is a promising surrogate marker to separate GAS from other types of ECA, including clear cell carcinoma.

Tumor genomic profiling is increasingly used to guide treatment strategy in cancer patients. We integrated tumor genomic, clinical demographic, and treatment response data to assess how prospective tumor-normal sequencing impacted treatment selection in patients with cervical cancer.Cervical cancers were prospectively analyzed using the MSK-IMPACT (Memorial Sloan Kettering Cancer Center - Integrated Mutation Profiling of Actionable Cancer Targets) next-generation sequencing panel. Clinical data, including histology, stage at diagnosis, treatment history, clinical trial enrollment and outcomes, date of last follow-up and survival status, were obtained from medical records.177 patients with cervical cancer (squamous, 69; endocervical adenocarcinoma, 50; gastric type, 22; adenosquamous, 21; and other, 15) underwent MSK-IMPACT testing. The most prevalent genomic alterations were somatic mutations or amplifications in PIK3CA (25%), ERBB2 (12%), KMT2C (10%), and KMT2D (9%). Furthermore, 13% of patients had high tumor mutational burden (TMB >10 mut/mB), 3 of which were also microsatellite instability-high (MSI-H). Thirty-seven percent of cases had at least one potentially actionable alteration designated as a level 3B mutational event according to the FDA-recognized OncoKB® tumor mutation database and treatment classification system. A total of 30 patients (17%) were enrolled on a therapeutic clinical trial, including 18 (10%) who were matched with a study based on their MSK-IMPACT results. Twenty patients (11%) participated in an immune checkpoint inhibition study for metastatic disease; 2 remain progression-free at >5 years follow-up.Tumor genomic profiling can facilitate the selection of targeted/immunotherapies, as well as clinical trial enrollment, for patients with cervical cancer.

Gastric-type endocervical adenocarcinoma (GAS), the predominant non-human papillomavirus cervical cancer, is highly aggressive with poor prognosis. No drugs are effective against advanced or recurrent GAS.

Gastric‐type endocervical adenocarcinoma (GEA) is the second most common subtype of endocervical adenocarcinoma and has a poor prognosis. Anti‐programmed death‐1 and anti‐programmed death‐ligand 1 (PD‐L1) inhibitors have emerged as a major treatment option for GEA; however, data on the expression of other immune checkpoints in GEA are limited. We analyzed the expression of T‐cell immunoglobulin and mucin‐domain containing‐3 (TIM‐3) and B7 homolog 3 protein (B7‐H3) in 58 GEA and investigated their prognostic significance as well as association with PD‐L1 expression and other known prognostic factors. Applying the tumor proportion score (TPS) with a cutoff of 1%, B7‐H3 and TIM‐3 were present in 48.3% and 17.2% of cases, respectively. Applying the combined positive score (CPS) with a cutoff of 1, TIM‐3 expression was present in 70.7% of cases. Moreover, the expression of three checkpoints (B7‐H3, TIM‐3, and PD‐L1) was incompletely overlapping. Patients with B7‐H3 positive tumors (by TPS) or TIM‐3 positive tumors (by TPS) had significantly worse recurrence‐free survival (RFS) and overall survival (OS) (log‐rank). Using CPS, patients with TIM‐3 positive tumors showed significantly worse RFS (log‐rank). Similarly, B7‐H3 positivity (by TPS) and TIM‐3 positivity (by TPS) were associated with worse RFS and OS in univariate analysis. TIM‐3 positivity (by CPS) was associated with worse RFS in univariate analysis and the final Cox multivariate analysis. In conclusion, our results show that (1) B7‐H3 and TIM‐3 are frequently expressed in GEA and their expression overlaps incompletely with PD‐L1; and (2) both B7‐H3 and TIM‐3 are independent negative prognostic markers in GEA.

Gastric-type adenocarcinoma (GAC) is the predominant subtype of HPV-independent endocervical adenocarcinoma, characterized by aggressive clinical behavior and poor prognosis. However, its tumor immune microenvironment (TIME) remains largely unexplored.

Human papillomavirus (HPV) infection is the primary cause of cervical cancer. HPV-mediated immune alterations are known to play crucial roles in determining viral persistence and host cell transformation. We sought to thoroughly understand HPV-directed immune alterations in cervical cancer by exploring publically available datasets.130 HPV positive and 7 HPV negative cervical cancer cases from The Cancer Genome Atlas were compared for differences in gene expression levels and functional enrichment. Analyses for copy number variation (CNV) and genetic mutation were conducted for differentially expressed immune genes. Kaplan-Meier analysis was performed to assess survival and relapse differences across cases with or without alterations of the identified immune signature genes.Genes up-regulated in HPV positive cervical cancer were enriched for various gene ontology terms of immune processes (P=1.05E-14~1.00E-05). Integrated analysis of the differentially expressed immune genes identified 9 genes that displayed either CNV, genetic mutation and/or gene expression changes in at least 10% of the cases of HPV positive cervical cancer. Genomic amplification may cause elevated levels of these genes in some HPV positive cases. Finally, patients with alterations in at least one of the nine signature genes overall had earlier relapse compared to those without any alterations. The altered expression of either TFRC or MMP13 may indicate poor survival for a subset of cervical cancer patients (P=1.07E-07).We identified a novel immune gene signature for HPV positive cervical cancer that is potentially associated with early relapse of cervical cancer.Copyright © 2018. Published by Elsevier Inc.

Gastric-type endocervical adenocarcinomas (GAS) are aggressive HPV-independent neoplasms with molecular alterations in TP53, STK11, CDKN2A, and SMAD4. Claudin-18 (CLDN18) has emerged as a useful marker to distinguish GAS from HPV-associated neoplasia. Its role in separating GAS from benign proliferations and exuberant endocervical glands is unknown. We studied the utility of immunohistochemistry for CLDN18, progesterone receptor (PR), and mutation surrogate stains (P53, STK11/LKB1, MTAP, SMAD4/DPC4) in 46 GAS, 12 benign gastric-type endocervical lesions, 54 benign Mullerian endocervical populations, and 11 HPV-associated endocervical adenocarcinomas. PD-L1 and HER2 immunostains were evaluated in GAS. Gastric-type lesions were more often positive for CLDN18 (100% benign, 78% GAS, most often well to moderately differentiated) compared to benign Mullerian endocervical specimens (all negative) and HPV-associated neoplasia (18%, always focal). Conversely, PR was negative in all gastric-type lesions and positive in 92% of benign Mullerian endocervical populations. GAS revealed aberrant/mutant expression of P53 in 35%, STK11/LKB1 in 25%, MTAP in 23%, and SMAD4/DPC4 in 9% of cases. Abnormal staining in at least one of these 4 mutation surrogate markers was present in 63% of GAS. HER2 score of 3+ was seen in 25% of GAS, and PD-L1 was positive in 37% based on a combined positive score. CLDN18 is a sensitive and highly specific marker of gastric-type benign and malignant endocervical lesions. Once a gastric-type phenotype is confirmed, mutation surrogate immunostains can be used to support a diagnosis of GAS. PD-L1 and HER2 expression is seen in a subset of GAS offering therapeutic options for this aggressive tumor.Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.

\n Few studies have explored HER2 status in cervical adenocarcinoma, particularly in the gastric‐type adenocarcinoma (GAC), a nonhuman‐papillomavirus‐related subtype with poor clinical outcomes. In this study, we investigated HER2 expression and amplification by immunohistochemistry (IHC) and fluorescence\n in situ\n hybridization (FISH) in 209 well annotated cervical adenocarcinomas diagnosed using the International Endocervical Adenocarcinoma Criteria and Classification. IHC identified HER2 protein expression in 57.4% (123/209) of adenocarcinomas, of which 62 were IHC 1+ (negative), 38 2+ (equivocal) and 23 3+ (positive).\n HER2\n amplification was found in 13 cases (6.2%) including 10 with IHC 3+ and 3 with IHC 2+. Among all the major histotypes of cervical adenocarcinoma,\n HER2\n amplification was most common in GAC cases with a frequency of 14.7% (5/34). Moreover,\n HER2\n amplification was more frequently associated with 2018 International Federation of Gynecology & Obstetrics (FIGO) stage III/IV, perineural involvement and ovarian spread (\n p\n  < 0.05) while IHC 3+ was more common in patients with lymphovascular invasion and ovarian involvement (\n p\n  < 0.05). Survival analysis indicated that FIGO stage III/IV, GAC, and p53 overexpression were associated with poor disease‐specific survival and tumor recurrence (\n p\n  < 0.05). In conclusion,\n HER2\n amplification was present in a subset of adenocarcinomas, and more common in GAC, pointing to a potential benefit from trastuzumab treatment. HER2 overexpression does not identify gene amplification status in cervical adenocarcinoma; therefore, FISH is suggested for both IHC positive and equivocal cases. Further investigation on more cases with longer follow‐up times is required to consolidate these findings.\n

The objective of this study was to elucidate the frequency and cytologic features of positive peritoneal washing cytology (PWC) in cervical gastric‐type adenocarcinoma (GAS) and to clarify the clinical significance of positive PWC.

Gastric‐type endocervical adenocarcinoma (GEA) is a rare malignant tumor that is not associated with high‐risk HPV infection, known for its high invasiveness and resistance to current treatments. This study assessed the effectiveness of anti‐angiogenic regimens in real‐world GEA patients.

Peutz–Jeghers syndrome (PJS) is a rare autosomal dominant disorder characterized by mucocutaneous pigmentation (e.g., perioral melanotic macules) and gastrointestinal hamartomatous polyps, with heightened cancer susceptibility. This report describes a 34-year-old Han Chinese ethnicity woman with familial Peutz–Jeghers syndrome (PJS) and stage IIA HPV-independent gastric-type endocervical adenocarcinoma following bevacizumab therapy. Initial concurrent chemoradiation (paclitaxel with either nedaplatin or cisplatin with volumetric modulated arc therapy) achieved partial response, while subsequent maintenance therapy combining bevacizumab with chemotherapy induced complete radiographic remission. Crucially, progressive fading of pathognomonic perioral melanotic macules demonstrated temporal correlation with bevacizumab administration, with sustained remission at 1-year follow-up. These findings challenge the conventional paradigm of PJS pigmentation as a static feature by demonstrating that VEGF-mediated angiogenesis concurrently drives carcinogenesis and melanin deposition. The case highlights three key implications, namely: (1) validation of bevacizumab’s dual therapeutic potential against PJS-associated malignancies and cutaneous manifestations, (2) proposal of mucocutaneous pigmentation as a dynamic biomarker for treatment response monitoring, and (3) urgent need for prospective clinical trials evaluating VEGF inhibition in PJS through longitudinal surveillance of oncologic control and pigment dynamics.

Gastric-type adenocarcinoma is the commonest human papillomavirus (HPV)-independent adenocarcinoma of the cervix. We report a rare case of a primary cervical gastric-type adenocarcinoma with malignant squamous elements (gastric-type adenosquamous carcinoma) in a 64-yr-old female. This is only the third report of a cervical gastric-type adenosquamous carcinoma. The tumor was p16 negative and molecular studies for HPV were negative. Next-generation sequencing showed pathogenic variants in BRCA1 and KRAS, as well as variants of unknown significance in CDK12 and ATM and homozygous deletion of CDKN2A/CDKN2B. Pathologists should be aware that not all cervical adenosquamous carcinomas are HPV-associated and the term gastric-type adenosquamous carcinoma is recommended when malignant squamous elements are present within a gastric-type adenocarcinoma. In reporting this case, we discuss the differential and the possible therapeutic options raised by the presence of pathogenic variants in BRCA1.Copyright © 2023 by the International Society of Gynecological Pathologists.

Invasive stratified mucin-producing carcinoma (ISMC) is a rare but aggressive variant of endocervical adenocarcinoma (EAC). The aim of this study was to investigate the differences in clinicopathological features, patient outcomes, and programmed death-ligand 1 (PD-L1) expression among ISMC, usual-type EAC (UEA), and gastric-type EAC (GEA).PD-L1 22C3 immunostaining was performed using 20 ISMCs, 20 UEAs, and 20 GEAs. Combined positive score (CPS) method was used to assess PD-L1 immunoreactivity.ISMC was diagnosed at a younger age and showed a more advanced stage and shorter survival than UEA. The disease-free survival (DFS) and overall survival (OS) rates of ISMC patients were lower than those of UEA but comparable to those of GEA. ISMC type was an independent prognostic factor for predicting short DFS [hazard ratio (HR)=2.790, 95% confidence interval (CI)=1.153-6.756] and OS (HR=6.071, 95%CI=1.257-29.327). All ISMCs showed PD-L1 over-expression with a mean CPS of 44.5 (range=10-100), which was higher than those of UEA (mean CPS=8.2) and GEA (mean CPS=6.5). PD-L1 positivity (CPS≥1) was also an independent prognostic factor for worse OS (HR=2.472, 95%CI=1.097-5.570). Despite PD-L1 over-expression, ISMC patients treated with pembrolizumab showed no clinical response.All examined ISMCs over-expressed PD-L1. ISMC showed higher PD-L1 expression than UEA and GEA and worse survival than UEA. PD-L1 over-expression was found to be a significant predictor for worse DFS and OS in patients with ISMC. Our data suggest that PD-L1 over-expression is associated with poor ISMC prognosis.Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.