Stratified Mucin-Producing Intraepithelial Lesion of the Cervix in an HPV-16 Positive Woman: A Rare Encounter.

BACKGROUND: Cervical cancer is the fourth most common cancer among women globally and has a strong association with Human Papillomavirus (HPV) infection. Stratified mucinproducing intraepithelial lesion (SMILE), a variant of Adenocarcinoma in situ (AIS), is a rare cervical precancer lesion that is often missed or detected incidentally. CASE PRESENTATION: The present case report briefs the finding of a 39-year-old woman who presented to the gynecological outpatient department with complaints of vaginal discharge for 6-8 months. She had no history of irregular menstrual cycles or postcoital bleeding. Her routine Pap smear revealed atypical squamous cells of undetermined significance (ASCUS) and was positive for HPV-16 type. Her cervical biopsy report revealed AIS and her histopathological report of hysterectomy revealed SMILE, a variant of AIS. DISCUSSION: The SMILE variant of AIS is a rare cervical precancerous lesion characterized by the morphological overlap of both squamous intraepithelial lesions and AIS. It is often difficult to diagnose on Pap smear and is commonly associated with high-risk HPV infections. The management of SMILE is the same as that for AIS, which is the excisional procedure followed by a hysterectomy if the margins are negative and depending on the fertility desires of the patient, followed by regular follow-up with HPV testing. CONCLUSION: SMILE is a rare variant of AIS, which is often missed on cytological screening of the cervix. It is commonly associated with high-risk types of HPV. Hence, incorporating HPV testing in the screening of cervical cancer is important and recommended to increase the overall sensitivity of screening for adenocarcinoma lesions.

Adenocarcinoma In Situ of the Uterine Cervix (AIS) Treated by Loop Electrosurgical Excision Procedure Strategy: An Observational Study.

OBJECTIVES: Evaluation of the results of treatment of adenocarcinoma in situ by loop electrosurgical excision procedure and the safety of a conservative strategy. METHODS: Identification of all cases of adenocarcinoma in situ treated by loop electrosurgical excision procedure at our institution and follow-up by a conservative strategy. Completeness of the identification of all cases was secured by data from the National Pathology Registry. The treatment strategy was based on cytologic follow-up performed by a general practitioner and, irrespective of margin status of the cone, only the results of the postoperative surveillance were indicative of further treatment. RESULTS: A total of 224 patients were identified. The overall recurrence rate with a mean follow-up time of 87.8 months was 7.6% (17/224). The recurrence rate in patients with involved margins was significantly higher than in patients with uninvolved margins, 15.7% vs 5.2%, respectively. Six recurrences were diagnosed at first examination 6 months postconization in patients with involved margins. They were treated with hysterectomy in 4 cases and reconization in 1 case. If involvement of margins alone had been an indication of further therapy (hysterectomy or reconization) immediately after conization, the conservative management strategy prevented 46 surgical procedures. Two cases of invasive cancer were diagnosed during follow-up, 150 months and 196 months after primary treatment, and after normal follow-up examinations. These 2 cases must be considered de novo cases and cannot be considered treatment failures. CONCLUSION: The conservative management strategy thus seems safe, and unnecessary surgical procedures were avoided.

Expression Changes in Programmed Death Ligand 1 from Precancerous Lesions to Invasive Adenocarcinoma in Subcentimeter Pulmonary Nodules: A Large Study of 2022 Cases in China.

PURPOSE: This large-scale, multicenter, retrospective observational study aimed to evaluate the clinicopathological and molecular profiles associated with programmed death-ligand 1 (PD-L1) expression in precancerous lesions and invasive adenocarcinoma in subcentimeter pulmonary nodules. PATIENTS AND METHODS: Patients with histologically confirmed atypical adenomatous hyperplasia (AAH), adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA), and invasive adenocarcinoma (ADC) were included. PD-L1 expression was evaluated at each center using a PD-L1 immunohistochemistry 22C3 pharmDx kit (Agilent, Santa Clara, CA, USA). The tumor proportion score (TPS) cutoff values were set at ≥ 1% and ≥ 50%. RESULTS: A total of 2022 nodules from 1844 patients were analyzed. Of these, 9 (0.45%) nodules had PD-L1 TPS ≥ 50%, 187 (9.25%) had PD-L1 TPS 1-49%, and 1826 (90.30%) had PD-L1 TPS < 1%. A total of 378 (18.69%), 1016 (50.25%), and 628 (31.06%) nodules were diagnosed as AAH/AIS, MIA, and ADC, respectively, by pathology. A total of 1377 (68.10%), 591 (25.67%), and 54 (2.67%) nodules were diagnosed as pure ground-glass opacity (GGO), mixed GGO, and solid nodules, respectively, by computed tomography. There was a significant difference between PD-L1 expression and anaplastic lymphoma kinase (ALK) mutation status (P < 0.001). PD-L1 expression levels were significantly different from those determined using the International Association for the Study of Lung Cancer (IASLC) grading system (P < 0.001). CONCLUSIONS: PD-L1 expression was significantly associated with radiological and pathological invasiveness and driver mutation status in subcentimeter pulmonary nodules. The significance of PD-L1 expression in the evolution of early-stage lung adenocarcinoma requires further investigation.

Impact of cervical excisional dimensions on endocervical margins status in adenocarcinoma in situ of the uterine cervix: A multicenter study from the FRANCOGYN group.

OBJECTIVE: Excisional procedures have a central role in the management of adenocarcinoma in situ of the cervix (AIS). We aimed to evaluate the relationship between the excisional specimen dimensions and the endocervical margin status. METHODS: We conducted a multicentric retrospective study in seven French centers. All cases with proven AIS on a colposcopic biopsy and undergoing an excisional procedure afterwards were included in the analysis. We evaluated the impact of excision length, along with the lateral and anteroposterior diameters on the endocervical margin status. An additional subgroup analysis of the impact of maternal age on endocervical margin status was also conducted. RESULTS: Of the 101 cases of AIS diagnosed on initial biopsy, 95 underwent a primary excisional procedure, among which 80% (n = 76/95) had uninvolved endocervical margins and 20% (n = 19/95) had positive endocervical margins. The excisional specimen length was not significantly related to the endocervical margin status. Conversely, both lateral and antero-posterior diameters were significantly correlated with the negative endocervical margins status: OR = 1,19, 95% CI [1.03, 1.40], p = 0.025, for the lateral diameter and OR = 1.34, 95% CI [1.14, 1.64], p = 0.001 for the antero-posterior diameter. The median lateral diameter was 20 mm, IQR (18, 24) in case of endocervical negative margins vs. 18 mm IQR (15, 24) in case of positive endocervical margins (p = 0.039), and the median anteroposterior diameter was 17 mm IQR (15, 20) in case of negative endocervical margins vs 14 mm IQR (11, 15) in case of positive endocervical margins (p = 0.004), respectively.  Additionally, in patients over 45 years old, endocervical margin were more likely to be positive despite similar excisional dimensions (7/17 (41%) of positive endocercival margins before 45 years old vs 12/78 (15%) after, p = 0.039) CONCLUSIONS: Endocervical margin statues were significantly related to the transverse diameters (lateral and anteroposterior diameters), but not to the excision specimen length. Reducing the excised length may lead to fewer post-procedure complications but would still allow to obtain a large proportion of negative endocervical margins.

Clinical and Sonographic Features of Noninvasive Follicular Thyroid Neoplasm With Papillary-Like Nuclear Features: A Retrospective Study.

ABSTRACT: This study was designed to investigate the clinical and sonographic features of noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTPs) as compared with classical papillary thyroid carcinoma (cPTC), follicular adenoma (FA), and follicular thyroid carcinoma (FTC). A total of 178 patients were enrolled in this study. The clinical characteristics and sonographic features of thyroid nodules were compared between NIFTP and cPTC or FA/FTC. All nodules were reclassified according to the Thyroid Ultrasound Imaging Reporting and Data System and American Thyroid Association guidelines classification. The mean size of NIFTP was 29.91 ± 14.71 mm, which was larger than that of cPTC ( P = 0.000). Significant difference was found in lymph node metastases between NIFTP and cPTC ( P = 0.000). Most NIFTPs showed solid composition, hypoechoic echogenicity, smooth margin, wider than tall shape, none echogenic foci, absence of halo, and perinodular vascularity, which were similar with FA and FTC. Compared with NIFTP, hypoechoic and very hypoechoic, taller than wide, irregular margin, punctate echogenic foci, absence of halo, and low vascularity were more commonly observed in cPTC. There were statistical differences both in American College of Radiology Thyroid Ultrasound Imaging Reporting and Data System and in American Thyroid Association classification between NIFTP and cPTC ( P < 0.05), but there were no significant differences between NIFTP and FTC/FA ( P > 0.05). The ultrasonographic characteristics of NIFTP were obviously different from cPTC but overlapped with FTC and FA. Ultrasound could help increase preoperative attention of NIFTP in an appropriate clinical setting, which may lead to a more conservative treatment approach.

Computed Tomography Findings for Predicting Invasiveness of Lung Adenocarcinomas Manifesting as Pure Ground-Glass Nodules.

Purpose: To comprehensively evaluate qualitative and quantitative features for predicting invasiveness of pure ground-glass nodules (pGGNs) using multiplanar computed tomography. Methods: Ninety-three resected pGGNs (16 atypical adenomatous hyperplasia [AAH], 18 adenocarcinoma in situ [AIS], 31 minimally invasive adenocarcinoma [MIA], and 28 invasive adenocarcinoma [IA]) were retrospectively included. Two radiologists analyzed qualitative and quantitative features on three standard planes. Univariable and multivariable logistic regression analyses were performed to identify features to distinguish the pre-invasive (AAH/AIS) from the invasive (MIA/IA) group. Results: Tumor size showed high area under the curve (AUC) for predicting invasiveness (.860, .863, .874, and .893, for axial long diameter [AXLD], multiplanar long diameter, mean diameter, and volume, respectively). The AUC for AXLD (cutoff, 11 mm) was comparable to that of the volume (P = .202). The invasive group had a significantly higher number of qualitative features than the pre-invasive group, regardless of tumor size. Six out of 59 invasive nodules (10.2%) were smaller than 11 mm, and all had at least one qualitative feature. pGGNs smaller than 11 mm without any qualitative features (n = 16) were all pre-invasive. In multivariable analysis, AXLD, vessel change, and the presence or number of qualitative features were independent predictors for invasiveness. The model with AXLD and the number of qualitative features achieved the highest AUC (.902, 95% confidence interval .833-.971). Conclusion: In adenocarcinomas manifesting as pGGNs on computed tomography, AXLD and the number of qualitative features are independent risk factors for invasiveness; small pGGNs (<11 mm) without qualitative features have low probability of invasiveness.

Comparison of the safety between cervical conization and hysterectomy for patients with cervical adenocarcinoma in situ.

OBJECTIVE: To compare the safety between cervical conization (CC) alone and hysterectomy for patients with adenocarcinoma in situ (AIS) of the cervix. METHODS: Patients diagnosed with AIS after CC during 2007-2021 were identified by computerized databases at Women's Hospital of Zhejiang University School of Medicine. A total of 453 AIS patients were divided into 2 groups according to uterus preservation: hysterectomy group (n=300) and CC(s) alone group (n=153). The prevalence of residual disease and disease recurrence was compared between patients treated by CC(s) alone and hysterectomy. The prevalence of residual disease in specimens from women who had a hysterectomy and repeat CC were compared between positive and negative margins of CC. The factors influencing residual disease and disease recurrence were assessed. RESULTS: Among 310 specimens from women who had a hysterectomy or repeat CC, the prevalence of residual disease was 50.6% (45/89) for a positive margin and 2.3% (5/221) for a negative margin (p=0.000). Four patients had recurrence of vaginal intraepithelial neoplasia in those treated by hysterectomy and one had recurrence of cervical squamous intraepithelial neoplasia in those treated by CC(s) alone. The prevalence of recurrence was 0.7% (1/153) for CC(s) alone and 1.3% (4/300) for hysterectomy (p=0.431). Hysterectomy did not influence residual disease or disease recurrence. CONCLUSION: CC is an efficacious and safe option for patients with AIS of the cervix provided the margin is negative.

Bronchiolar adenoma/ciliated muconodular papillary tumor mixed with adenocarcinoma in situ in the same tumor.

Bronchiolar adenoma (BA)/ciliated muconodular papillary tumor (CMPT) is defined as a benign tumor composed of epithelial and basal cells. Recently, some cases with driver mutations or malignant transformation have been observed. Thus, whether BA/CMPT is benign or malignant remains controversial. We herein report an extremely rare case of a 68-year-old woman with a CMPT accompanied by adenocarcinoma in situ (AIS). BA/CMPT existed inside the AIS. The BA/CMPT component did not show any driver mutations; however, the AIS component had an EGFR driver mutation in exon 19. The accumulation of cases and further studies are needed to discuss the malignant potential of BA/CMPT.

Ten-year follow-up of lung cancer patients with resected adenocarcinoma in situ or minimally invasive adenocarcinoma: Wedge resection is curative.

OBJECTIVE: This study aimed to reveal the long-term outcomes of patients with lung cancer with adenocarcinoma in situ or minimally invasive adenocarcinoma after resection, in the context of the different surgical resection types. METHODS: Patients with lung adenocarcinoma who underwent resection between December 2007 and December 2012 were reviewed. Patients with pathological adenocarcinoma in situ or minimally invasive adenocarcinoma were enrolled. Postoperative survival and risk of developing second primary lung cancer were analyzed. RESULTS: After reevaluating the histological findings of 1696 patients with lung adenocarcinoma, we enrolled 53 with adenocarcinoma in situ and 72 with minimally invasive adenocarcinoma for analyses. Of all 125 patients with adenocarcinoma in situ/minimally invasive adenocarcinoma, 86 (68.8%) were female, 114 (91.2%) were nonsmokers, and most of them (78, 62.4%) underwent wedge resection. The median follow-up period after surgery was 111 months. The 10-year recurrence-free survivals of adenocarcinoma in situ and minimally invasive adenocarcinoma were all 100%, and the 10-year overall survivals of adenocarcinoma in situ and minimally invasive adenocarcinoma were 98.1% and 97.2%, respectively. There was no difference in 10-year recurrence-free survival between patients who underwent lobectomy and wedge resection. EGFR mutations were detected in 63.1% (41/65) of patients who underwent mutational analysis. The risks of developing second primary lung cancer for adenocarcinoma in situ and minimally invasive adenocarcinoma 10 years after resection were 8.4% and 4.3% (P = .298), respectively, and were not correlated with EGFR mutation status (P = .525). CONCLUSIONS: Pathological adenocarcinoma in situ and minimally invasive adenocarcinoma have no recurrence during 10-year follow-up after resection, regardless of surgical procedure types. Surgery is curative for these patients, and wedge resection is the preferred surgical procedure for nodules in the proper location.

Conservative Treatment for Cervical Adenocarcinoma In Situ: Long-Term Results.

OBJECTIVE: This study aimed to evaluate the effectiveness of conservative treatment for cervical adenocarcinoma in situ (AIS). MATERIALS AND METHODS: This is a retrospective study on women with histologically confirmed AIS on cervical loop electrosurgical excision procedure specimen, treated conservatively between 2008 and 2020 in our center, Ospedale Maggiore Policlinico, Milan. The main outcome investigated was the risk of recurrence defined as a subsequent finding of recurrent AIS or invasive adenocarcinoma in a long-term follow-up. The disease-free survival curve was computed using the Kaplan-Meyer method. All patients underwent colposcopy with endocervical curettage and cytology every 6 months for the first 2 years after initial surgery and then annual cytology. RESULTS: Thirty women, aged 26 to 51 years, with histologically proven AIS on excisional specimen with negative margins, negative apex, and negative endocervical curettage were included. The median follow-up was 5.4 years. One woman had a recurrence of AIS after 8 years of follow-up and underwent total hysterectomy. No invasive cervical disease was detected during surveillance. CONCLUSIONS: Women with cervical AIS can be managed conservatively by an excisional procedure, provided that the margins are free and a close and long-term follow-up is guaranteed.

A triple-classification for the evaluation of lung nodules manifesting as pure ground-glass sign: a CT-based radiomic analysis.

OBJECTIVES: To construct a noninvasive radiomics model for evaluating the pathological degree and an individualized treatment strategy for patients with the manifestation of ground glass nodules (GGNs) on CT images. METHODS: The retrospective primary cohort investigation included patients with GGNs on CT images who underwent resection between June 2015 and June 2020. The intratumoral regions of interest were segmented semiautomatically, and radiomics features were extracted from the intratumoral and peritumoral regions. After feature selection by ANOVA, Max-Relevance and Min-Redundancy (mRMR) and Least Absolute Shrinkage and Selection Operator (Lasso) regression, a random forest (RF) model was generated. Receiver operating characteristic (ROC) analysis was calculated to evaluate each classification. Shapley additive explanations (SHAP) was applied to interpret the radiomics features. RESULTS: In this study, 241 patients including atypical adenomatous hyperplasia (AAH) or adenocarcinoma in situ (AIS) (n = 72), minimally invasive adenocarcinoma (MIA) (n = 83) and invasive adenocarcinoma (IAC) (n = 86) were selected for radiomics analysis. Three intratumoral radiomics features and one peritumoral feature were finally identified by the triple RF classifier with an average area under the curve (AUC) of 0.960 (0.963 for AAH/AIS, 0.940 for MIA, 0.978 for IAC) in the training set and 0.944 (0.955 for AAH/AIS, 0.952 for MIA, 0.926 for IAC) in the testing set for evaluation of the GGNs. CONCLUSION: The triple classification based on intra- and peritumoral radiomics features derived from the noncontrast CT images had satisfactory performance and may be used as a noninvasive tool for preoperative evaluation of the pure ground-glass nodules and developing of individualized treatment strategies.

Adenocarcinoma in situ or early-stage cervical cancer is a risk factor for preterm delivery after cervical conization: a multicenter observational study.

OBJECTIVE: Pregnancy after conization is associated with a high risk of preterm delivery. However, because risk factors for preterm delivery after conization remain unknown, we conducted a multicenter observational study to investigate risk factors associated with preterm delivery. METHODS: We selected patients who had previously undergone conization and reviewed medical records from 18 hospitals in cooperation with Keio University School of Medicine between January 2013 and December 2019. Women were classified as nulliparous and primiparous, and a multiple logistic regression analysis was performed to evaluate the relative contributions of the various maternal risk factors for preterm delivery (i.e. delivery before 37 gestational weeks). RESULTS: Among 409 pregnant women after conization, 68 women delivered preterm (17%). The incidence of nulliparity (p = .014) was higher and a history of preterm delivery (p = .0010) was more common in the preterm delivery group than in the term delivery group. Furthermore, the proportion of women diagnosed with adenocarcinoma in situ (AIS) and cervical cancer in the preterm delivery group was higher than that in the term delivery group (p = .0099 and .0004, respectively). In multiple regression models in nulliparous women, cervical cancer or AIS (Odds ratio [OR]: 4.16, 95% CI: 1.26-13.68, p = .019) and a short cervix in the second trimester (OR: 13.41, 95% CI: 3.88-46.42, p < .0001) increased the risk of preterm delivery. Furthermore, a history of preterm delivery (OR: 7.35, 95% CI: 1.55-34.86, p = .012), cervical cancer or AIS (OR: 5.07, 95% CI: 1.24-20.73, p = .024), and a short cervix in the second trimester (OR: 4.29, 95% CI: 1.11-16.62, p = .035) increased the risk of preterm delivery in the multiple regression models in primiparous women. CONCLUSION: Pregnant women who previously underwent conization are at risk for preterm delivery. The histological type of AIS and cervical cancer was evaluated as a risk factor for preterm delivery. KEY MESSAGESPrior preterm delivery, presence of a short cervix, and cervical cancer or AIS were predictors of preterm delivery after conization.The depth of conization in cervical cancer or AIS group was significantly larger than that in the CIN group.

Cervical adenocarcinoma in situ during pregnancy and subsequent fertility-sparing therapy challenge.

OBJECTIVE: Adenocarcinoma in situ (AIS) of the cervix is a premalignant lesion, and a precursor of invasive disease. It is less frequent than its squamous counterpart. During pregnancy, AIS is a scarcely described scenario, whose diagnosis barely differs from non-pregnant patients. Its management is challenging with hysterectomy being the definitive treatment. However, its high incidence in young patients makes fertility-sparing management an approachable option for selected patients. The objective of this study is twofold. Firstly, we describe a case of a patient with AIS during pregnancy and the postpartum period. Secondly, the available literature is reviewed. METHODS: Retrospective medical record review of a single case and a medical literature search in Pubmed of AIS cases in pregnant women. RESULTS: A 31-year-old woman with cervical AIS diagnosed during pregnancy underwent serial fertility-sparing surgeries including a loop electrosurgical excision procedure and endocervical curettage during the second trimester, and a re-conization and a simple traquelectomy during the postpartum period, until negative margins were achieved. Upon reviewing the literature from 1965 to 2020, 23 other cases were found. CONCLUSION: Surgical management of cervical AIS during pregnancy is a safe procedure. Subsequent conservative surgeries imply a real challenge to preserve fertility.

Endocervical adenocarcinoma in situ-from Papanicolaou test to hysterectomy: a series of 74 cases.

INTRODUCTION: Endocervical adenocarcinoma in situ (AIS) is not always identified on cervical Papanicolaou (Pap) test cytology because the Pap test has relatively low sensitivity for the diagnosis endocervical glandular lesions. We performed a retrospective study to determine the relative sensitivity of different diagnostic approaches, including Pap tests, cervical biopsy and/or endocervical curettage, loop electrosurgical excision procedure (LEEP), and hysterectomy specimens. METHODS: Cases of endocervical AIS diagnosed from August 2005 to January 2019 were retrieved from our institution's pathology databases, and their clinicopathologic features were reviewed. RESULTS: A total of 74 patients with endocervical AIS with or without concurrent squamous intraepithelial lesions or cervical neoplasms were identified. Their mean age at diagnosis was 39.9 years. More than one half of the cases of AIS were not detected from screening Pap tests but were diagnosed during histologic examination of cervical biopsy or endocervical curettage, LEEP, or cone biopsy specimens (~66%). Only a few patients had had a definitive diagnosis of AIS from the Pap tests (10.8%). Other abnormal glandular cytology included atypical glandular cells, not otherwise specified (16.2%), atypical glandular cells favoring neoplasia (5.4%), and atypical glandular cells suspicious for malignancy (1.3%). Abnormal squamous cytology was common in the study population (54%), with high-grade squamous intraepithelial lesion the most common finding (30%). AIS was diagnosed in 31 of 42 cervical biopsies or curettages, with 16 cases an incidental finding and 15 cases confirming previous abnormal glandular cytology. In addition, AIS was identified in 51 of 53 LEEPs. Approximately 41.5% of those undergoing LEEP had a previous diagnosis of AIS, and 54.7% of the cases were incidental findings. More than one half of the AIS cases harbored significant concurrent cervical lesions, including 26.7% with high-grade squamous intraepithelial lesion, 5.7% with low-grade squamous intraepithelial lesion, 1.9% with invasive squamous cell carcinoma, 20.9% with invasive adenocarcinoma, and 6.7% with microinvasive adenocarcinoma. CONCLUSIONS: Our results have demonstrated that the ability to detect AIS with routine screening Pap testing or biopsy/curettage has variable efficacy depending on the screening methods. Given the relatively low combined sensitivity of Pap testing and biopsy/endocervical curettage in the diagnosis of AIS, all LEEPs and cervical cone biopsies performed for squamous cell abnormalities should be thoroughly evaluated for glandular lesions.

Surgery for pre- and minimally invasive lung adenocarcinoma.

OBJECTIVE: Adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA) are the pre- and minimally invasive forms of lung adenocarcinoma. We aimed to investigate safety results and survival outcomes following different types of surgical resection in a large sample of patients with AIS/MIA. METHODS: Medical records of patients with lung AIS/MIA who underwent surgery between 2012 and 2017 were retrospectively reviewed. Clinical characteristics, surgical types and complications, recurrence-free survival, and overall survival were investigated. RESULTS: A total of 1644 patients (422 AIS and 1222 MIA) were included. The overall surgical complication rate was significantly lower in patients receiving wedge resection (1.0%), and was comparable between patients undergoing segmentectomy (3.3%) or lobectomy (5.6%). Grade ≥ 3 complications occurred in 0.1% of patients in the wedge resection group, and in a comparable proportion of patients in the segmentectomy group (1.5%) and the lobectomy group (1.5%). There was no lymph node metastasis. The 5-year recurrence-free survival rate was 100%. The 5-year overall survival rate in the entire cohort was 98.8%, and was comparable among the wedge resection group (98.8%), the segmentectomy group (98.2%), and the lobectomy group (99.4%). CONCLUSIONS: Sublobar resection, especially wedge resection without lymph node dissection, may be the preferred surgical procedure for patients with AIS/MIA. If there are no risk factors, postoperative follow-up intervals may be extended. These implications should be validated in further studies.

PTEN Loss and ARID1A Mutation in an HPV-positive Metastatic Adenocarcinoma Diagnosed Almost 18 yr After an Intact Cone Excision for Endocervical Adenocarcinoma In Situ.

There have been previous reports of neoplasms with the morphology of endocervical adenocarcinoma in situ (AIS) that secondarily involve the ovaries, presumably through transtubal spread, with a smaller subset metastasizing to distant sites. These ovarian metastases have been discovered up to 7 yr postexcision of the endocervical lesion, consistent with the known potential for overtly invasive cervical carcinomas to recur late after primary curative management. Herein, we present a case of a premenopausal woman with a pelvic mass classified as metastatic human papillomavirus (HPV)-associated endocervical adenocarcinoma (p16-block immunoreactive, high-risk HPV positive by in situ hybridization with PTEN loss, ARID1A, and PBRM1 mutations detected by qualitative next-generation sequencing), identified 17.7 yr (212 mo) after a fertility-sparing cone excision with negative margins for endocervical AIS [HPV-associated, p16-block immunoreactive; PTEN, and BAF250a (ARID1a) expression retained]. Our case highlights: (1) the potential for a subset of lesions with the morphology of AIS to metastasize, and the extraordinarily long timeframe (almost 18 y, the longest reported to date) during which metastases may still be identified; (2) alterations in PTEN and ARID1A may play a role in the progression of a subset of endocervical carcinomas; and (3) the need for studies to evaluate the utility of incorporating ovarian/pelvic imaging into surveillance protocols following fertility-sparing excisions or ovarian-preserving hysterectomies, during the management of endocervical adenocarcinomas, as well as the need to counsel patients about the small but real risk of delayed discovery of ovarian metastases following fertility-preserving surgeries for AIS.

[Risk stratified management of cervical adenocarcinoma in situ based on cone margin state].

Objective: To investigate the hierarchical management scheme of cervical adenocarcinoma in situ (AIS) based on cervical conization margin state. Methods: All medical records of 249 patients diagnosed as AIS by loop electrosurgical excision procedure (LEEP) conization from Jan. 2010 to Dec. 2015 in Obstetrics and Gynecology Hospital of Fudan University were retrospectively reviewed, to explore the relationship between the status of the resection margin and the residual lesion after LEEP, and the multivariate logistic regression method was used to analyze the related factors that affect the residual lesion after LEEP in cervical AIS patients. Results: (1) The age of 249 cervical AIS patients was (40±8) years old (range: 23-71 years old). Of the 249 patients, 19 (7.6%, 19/249) had residual lesions; 69 cases were pathologically diagnosed as AIS after LEEP, and the residual lesion rate was 13.0% (9/69), which was significantly higher than that of AIS + high-grade squamous intraepithelial lesion [5.6% (10/180); χ2=3.968,P=0.046]; 33 cases were multifocal lesions, the residual rate of lesions was 21.2% (7/33), which was significantly higher than that of single focal lesions patients [5.6% (12/216); χ2=7.858, P=0.005]; 181 patients underwent endocervical curettage (ECC) before surgery, the residual rate of lesions in ECC-positive patients was 14.0% (14/100) , significantly higher than that of ECC-negative patients [4.9% (4/81); χ2=4.103, P=0.043]. (2) Among 249 cases of AIS patients, the positive rate of resection margins after LEEP was 35.3% (88/249); the residual rate of lesions in patients with positive resection margins (14.8%, 13/88) was significantly higher than those with negative margins [3.8%(6/156); χ2=9.355, P=0.002]. The age of patients underwent total hysterectomy after LEEP was (43±7) years old, which was significantly higher than that of patients who did not undergo total hysterectomy [(37±8) years old; t=6.518, P<0.01].Among the patients underwent total hysterectomy after LEEP, 3 cases (2.0%, 3/152) had fertility requirements, while 38 cases (39.2%, 38/97) did not underwent total hysterectomy, the difference between the two groups was statistically significant (χ2=59.579, P<0.01). Among the 152 patients who underwent total hysterectomy after LEEP, the residual rate of lesions was 11.8% (18/152); the residual rate of lesions in patients with positive resection margins was significantly higher than that of patients with negative resection margins [18.8% (12/64) vs 7.0% (6/86); χ2=4.861, P=0.028]. The median follow-up time of 97 patients who did not undergo total hysterectomy after LEEP was 32 months (range: 4-70 months). During the follow-up period, 3 cases of cervical AIS recurrence (3.1%, 3/97) and were followed by hysterectomy,no invasive adenocarcinoma were seen. (3) Multivariate logistic regression analysis showed that the positive resection margin (OR=4.098, 95%CI: 1.235-13.595, P=0.021), multifocal lesions (OR=5.464, 95%CI: 1.494-19.981, P=0.010) were independent risk factors that affected the residual lesions in patients with cervical AIS after LEEP. Conclusions: The cervical AIS patients after LEEP conization suggested be stratified by cone margin state as the first-line stratified index, age and fertility needs as the second-line stratified management index. The individualized management plan should be developed based on comprehensive assessment of high-risk factors of residual lesions.

Cervical intraepithelial neoplasia and the risk of spontaneous preterm birth: A Dutch population-based cohort study with 45,259 pregnancy outcomes.

BACKGROUND: Excisional procedures of cervical intraepithelial neoplasia (CIN) may increase the risk of preterm birth. It is unknown whether this increased risk is due to the excision procedure itself, to the underlying CIN, or to secondary risk factors that are associated with both preterm birth and CIN. The aim of this study is to assess the risk of spontaneous preterm birth in women with treated and untreated CIN and examine possible associations by making a distinction between the excised volume of cervical tissue and having cervical disease. METHODS AND FINDINGS: This Dutch population-based observational cohort study identified women aged 29 to 41 years with CIN between 2005 and 2015 from the Dutch pathology registry (PALGA) and frequency matched them with a control group without any cervical abnormality based on age at and year of pathology outcome (i.e., CIN or normal cytology) and urbanization (<100,000 inhabitants or ≥100,000 inhabitants). All their 45,259 subsequent singleton pregnancies with a gestational age ≥16 weeks between 2010 and 2017 were identified from the Dutch perinatal database (Perined). Nineteen potential confounders for preterm birth were identified. Adjusted odds ratios (ORs) were calculated for preterm birth comparing the 3 different groups of women: (1) women without CIN diagnosis; (2) women with untreated CIN; and (3) women with treated CIN prior to each childbirth. In total, 29,907, 5,940, and 9,412 pregnancies were included in the control, untreated CIN, and treated CIN group, respectively. The control group showed a 4.8% (1,002/20,969) proportion of spontaneous preterm birth, which increased to 6.9% (271/3,940) in the untreated CIN group, 9.5% (600/6,315) in the treated CIN group, and 15.6% (50/321) in the group with multiple treatments. Women with untreated CIN had a 1.38 times greater odds of preterm birth compared to women without CIN (95% confidence interval (CI) 1.19 to 1.60; P < 0.001). For women with treated CIN, these odds 2.07 times increased compared to the control group (95% CI 1.85 to 2.33; P < 0.001). Treated women had a 1.51 times increased odds of preterm birth compared to women with untreated CIN (95% CI 1.29 to 1.76; P < 0.001). Independent from cervical disease, a volume excised from the cervix of 0.5 to 0.9 cc increased the odds of preterm birth 2.20 times (37/379 versus 1,002/20,969; 95% CI 1.52 to 3.20; P < 0.001). These odds further increased 3.13 times and 5.93 times for women with an excised volume of 4 to 8.9 cc (90/724 versus 1,002/20,969; 95% CI 2.44 to 4.01; P < 0.001) and ≥9 cc (30/139 versus 1,002/20,969; 95% CI 3.86 to 9.13; P < 0.001), respectively. Limitations of the study include the retrospective nature, lack of sufficient information to calculate odds of preterm birth <24 weeks, and that the excised volume could only be calculated for a select group of women. CONCLUSIONS: In this study, we observed a strong correlation between preterm birth and a volume of ≥0.5 cc excised cervical tissue, regardless of the severity of CIN. Caution should be taken when performing excisional treatment in women of reproductive age as well as prudence in case of multiple biopsies. Fertile women with a history of performing multiple biopsies or excisional treatment for CIN may benefit from close surveillance during pregnancy.

Gastric adenocarcinoma of fundic gland (chief cell predominant type) coexisting with well differentiated intestinal adenocarcinoma: A case report.

RATIONALE: Gastric adenocarcinoma of fundic gland (chief cell predominant type) (GA-FG-CCP) is a new, rare variant of gastric adenocarcinoma, which is characterized by mild nuclear atypia and specific immunohistochemical markers. PATIENT CONCERNS: An 84-year-old Chinese man was referred to our hospital for endoscopic resection of a gastric lesion. INTERVENTIONS: We performed endoscopic submucosal dissection, and successfully removed the lesion. DIAGNOSIS: Esophago gastroduodenoscopy showed a slightly elevated lesion with a diameter of 22 mm in the posterior wall of cardia. Magnifying endoscopy with narrow band imaging revealed an abnormal microsurface and microvessels on the tumor surface. Endoscopic ultrasonography revealed a hypoechoic mass located in the first layer. The pathological diagnosis of the biopsy specimens indicated that the tumor was high grade intraepithelial neoplasia. The pathological diagnosis differed between the superficial and deeper part of the lesion. The superficial part was composed of a tubular structure with prominent atypia and was diagnosed as well differentiated intestinal adenocarcinoma. The deeper part was composed of a well-differentiated tubular adenocarcinoma mimicking the fundic gland cells, mainly the chief cells. The tumor cells showed mild nuclear atypia and was positive for pepsinogen-I (PG-I) and mucin-6 (MUC6). This deeper part was diagnosed as GA-FG-CCP. OUTCOMES: The tumor was successfully removed. This patient had no discomfort during the follow-up period (10 months). LESSONS: We present a rare case of GA-FG-CCP coexisted with well-differentiated tubular adenocarcinoma. GA-FG-CCP exists in the deep mucosal layer and the muscularis mucosa, which could not be found under endoscopy, but could be discerned in pathology with mild nuclear atypia and special biomarkers.