Impact of Patient-Directed Cytology Results Correspondence Program on Follow-Up of High-Grade Pap Tests.

OBJECTIVE: Proper follow-up of high-grade (HG) Pap tests is critical to the prevention of cervical cancer. This study evaluated the impact of a patient-directed cytology results correspondence program on follow-up of HG Pap tests among at-risk women aged 21 to 69 in Ontario. METHODS: A cohort study with a historical control was used to investigate the impact of a result letter on adherence to follow-up after an HG Pap test. Analyses were conducted on an intention-to-treat basis. The intervention group was defined as women with an HG Pap test in 2014-2016, and the control group included women with an HG Pap test in 2010-2012. Follow-up was defined as a colposcopy or related treatments within 6 months of an HG Pap test. Factors that could influence adherence to follow-up were included as covariates in a multivariable logistic regression model (Canadian Task Force Classification II-2). RESULTS: The study population comprised 7088 women in the intervention group and 6887 women in the non-intervention group. The follow-up rate in the intervention group was 86.2% compared with 81.0% in the non-intervention group. Controlling for covariates, women in the intervention group were more likely to have a follow-up (adjusted odds ratio 1.5; 95% confidence interval 1.3-1.6). Other significant factors included being registered to a family physician and the physician's gender. CONCLUSIONS: A patient-directed correspondence program that provides Pap test results directly to the woman may reduce loss to follow-up for an HG abnormality, with an increased likelihood that these women will seek and complete a colposcopy and related treatment.

RANZCOG Fellows' adherence to guidelines following cytological prediction of cervical adenocarcinoma-in-situ: Cause for concern?

BACKGROUND: For Australian women with screen-detected adenocarcinoma-in-situ (AIS), an excisional biopsy is mandatory for further assessment, treatment, and to exclude the presence of cervical adenocarcinoma. The only exclusion to this rule is if the woman has a clinically evident invasive cervical malignancy. Excisional treatments should be tailored according to a patient's age and future obstetric needs. To date, practitioner compliance with this recommendation has not been investigated. AIMS: To investigate clinical management for patients with a cytological test result predicting AIS. Secondary aims were to report the most severe histological findings of excisional biopsy specimens following cytological prediction of AIS and investigate treatment outcomes for conservatively managed patients with biopsy-confirmed AIS. MATERIALS AND METHODS: A retrospective, population-based cohort study was conducted. Cases were ascertained from the Tasmanian and Western Australia Cervical Screening Registries. Cytology and histology results for women with an index cervical smear reporting AIS from 2001 to 2012 were reviewed. RESULTS: Three hundred and twenty-one women (age range 18-69 years) had an index smear reporting AIS. Cervical cancer was diagnosed in 62 (19.3%) patients within the study cohort. Twenty-one of 321 patients (6.7%) were not initially managed according to the 2005 NHMRC Guidelines for the management of asymptomatic women with screen-detected abnormalities, including two women diagnosed with an occult cancer following a total hysterectomy. CONCLUSIONS: A minority of women were not managed in accordance with guidelines. This is of concern given that nearly one in five women with a smear predicting AIS had a final diagnosis of cervical cancer.

Treating Second Breast Events After Breast-Conserving Surgery for Ductal Carcinoma in Situ.

Background: Because of screening mammography, the number of ductal carcinoma in situ (DCIS) survivors has increased dramatically. DCIS survivors may face excess risk of second breast events (SBEs). However, little is known about SBE treatment or its relationship to initial DCIS care. Methods: Among a prospective cohort of women who underwent breast-conserving surgery (BCS) for DCIS from 1997 to 2008 at institutions participating in the NCCN Outcomes Database, we identified SBEs, described patterns of care for SBEs, and examined the association between DCIS treatment choice and SBE care. Using multivariable regression, we identified features associated with use of mastectomy, radiation therapy (RT), or antiestrogen therapy (AET) for SBEs. Results: Of 2,939 women who underwent BCS for DCIS, 83% received RT and 40% received AET. During the median follow-up of 4.2 years, 200 women (6.8%) developed an SBE (55% ipsilateral, 45% invasive). SBEs occurred in 6% of women who underwent RT for their initial DCIS versus 11% who did not. Local treatment for these events included BCS (10%), BCS/RT (30%), mastectomy (53%), or none (6%); only 28% of patients received AET. Independent predictors of RT or mastectomy for SBEs included younger age, shorter time to SBE diagnosis, and RT or AET for the initial DCIS. Conclusions: A sizable proportion of patients with SBEs were treated with mastectomy, most especially those who previously received RT for their initial DCIS and those who developed an ipsilateral SBE. Despite the occurrence of an SBE, relatively few patients received AET. Future studies should investigate optimal treatment approaches for SBEs, including the benefit of mastectomy versus lumpectomy for an ipsilateral SBE and the benefit of AET for a hormone-receptor-positive SBE contingent on AET use for the initial DCIS diagnosis.

Comparing treatment and outcomes of ductal carcinoma in situ among women in Missouri by race.

PURPOSE: To investigate whether treatment (surgery, radiation therapy, and endocrine therapy) contributes to racial disparities in outcomes of ductal carcinoma in situ (DCIS). PATIENTS AND METHODS: The analysis included 8184 non-Hispanic White and 954 non-Hispanic Black women diagnosed with DCIS between 1996 and 2011 and identified in the Missouri Cancer Registry. Logistic regression models were used to estimate odds ratios (ORs) of treatment for race. We used Cox proportional hazards regression models to estimate hazard ratios (HRs) of ipsilateral breast tumor (IBT) and contralateral breast tumor (CBT) for race. RESULTS: There was no significant difference between Black and White women in utilization of mastectomy (OR 1.16; 95 % CI 0.99-1.35) or endocrine therapy (OR 1.19; 95 % CI 0.94-1.51). Despite no significant difference in underutilization of radiation therapy (OR 1.14; 95 % CI 0.92-1.42), Black women had higher odds of radiation delay, defined as at least 8 weeks between surgery and radiation (OR 1.92; 95 % CI 1.55-2.37). Among 9138 patients, 184 had IBTs and 326 had CBTs. Black women had a higher risk of IBTs (HR 1.69; 95 % CI 1.15-2.50) and a comparable risk of CBTs (HR 1.19; 95 % CI 0.84-1.68), which were independent of pathological features and treatment. CONCLUSION: Racial differences in DCIS treatment and outcomes exist in Missouri. This study could not completely explain the higher risk of IBTs in Black women. Future studies should identify differences in timely initiation and completion of treatment, which may contribute to the racial difference in IBTs after DCIS.

Diagnosis and Management of Adenocarcinoma in Situ: A Society of Gynecologic Oncology Evidence-Based Review and Recommendations.

This publication represents an extensive literature review with the goal of providing guidelines for the evaluation and management of cervical adenocarcinoma in situ (AIS). The authors drafted the guidelines on behalf of the Society of Gynecologic Oncology, and the guidelines have been reviewed and endorsed by the ASCCP. These guidelines harmonize with the ASCCP Risk-Based Management Consensus Guidelines and provide more specific guidance beyond that provided by the ASCCP guidelines. Examples of updates include recommendations to optimize the diagnostic excisional specimen, AIS management in the setting of positive compared with negative margins on the excisional specimen, surveillance and definitive management after fertility-sparing treatment, and management of AIS in pregnancy. The increasing incidence of AIS, its association with human papillomavirus-18 infection, challenges in diagnosis owing to frequent origin within the endocervical canal, and the possibility of skip lesions all make AIS a unique diagnosis whose management needs to be differentiated from the management of the more prevalent squamous cell dysplasia.

Invasive and in situ cervical cancer associated with pregnancy: analysis from the French cancer network (CALG: Cancer Associé à La Grossesse).

PURPOSE: To describe the oncologic and obstetric outcomes of patients diagnosed with invasive cervical cancer (ICC) and in situ adenocarcinoma (ISA) during pregnancy or during the year following delivery. METHODS: This retrospective observational study involved a cohort of 28 patients diagnosed with invasive cervical cancer (20 patients) or in situ adenocarcinoma (eight patients) during pregnancy or during the year following delivery who received expert opinion from physicians of the Cancer Associé à La Grossesse (CALG) network between 2005 and 2018. Descriptive results were expressed in median, range and interquartile range (IQR). RESULTS: Between 2005 and 2018, 20 patients with ICC and eight with ISA received expert opinion from physicians of the CALG network. Both ICC and ISA were mostly diagnosed during pregnancy with a median term at diagnosis of 23.3 weeks of gestation (WG) for ICC and 7.3 WG for ISA. Overall, the median age at diagnosis for both ICC and ISA was 33 years. Most ICCs (n = 9) had FIGO stage ≥ IB2 and five underwent neoadjuvant chemotherapy at a median term of 22.5 WG. Seventeen patients with ICC underwent surgery. Three patients had medical termination of the pregnancy. Two patients experienced recurrence and three died. Median time of follow-up was 59.3 months (IQR 30.5-129.2). CONCLUSION: Management of cervical cancer during pregnancy is challenging especially in terms of maternal outcomes with a relative poor prognosis requiring a multidisciplinary expert advice.

PIN-like (Ductal) Adenocarcinoma of the Prostate.

Prostatic intraepithelial neoplasia like (PIN-like ductal) carcinoma are rare tumors characterized by crowded, often cystically dilated glands architecturally resembling high-grade prostatic intraepithelial neoplasia, lined by malignant pseudostratified columnar epithelium. The largest prior series studied 9 radical prostatectomies (RPs) and suggested a behavior similar to Gleason score 6. We sought to investigate this rare tumor within a larger series. PIN-like carcinoma cases were identified from in-house and consultation files from 2008 to 2017. A total of 190 total cases were identified (in-house cases n=8, 4.2%, consult cases n=182, 95.8%); the diagnosis of PIN-like carcinoma was made on needle biopsy (n=181), transurethral resection (n=5) and RP (n=4). The average age was 70 years. The average number of cores with involvement by PIN-like carcinoma was 2 (1 to 12). The average maximum percentage by a PIN-like carcinoma component of any core was 43.5% (5% to 90%). In 58/181 (32.0%) biopsy cases, due to selective parts having been submitted for consultation, it was unknown whether there was an association with acinar carcinoma. A total of 72 cases showed exclusively PIN-like carcinoma. Highest grade groups (GGs) on biopsies with known acinar or papillary/cribriform ductal carcinomas were GG1 (n=23, 45.1%), GG2 (n=14, 27.5%), GG3 (n=9, 17.6%), GG4 (n=4, 7.8%), and GG5 (n=1, 2.0%). Of 44 cases where the patient would be considered eligible for active surveillance, 18 (41.0%) underwent RP. RP slides were available in 16 cases; 3 (18.8%) cases diagnosed on biopsy did not show PIN-like carcinoma on review of RP slides. PIN-like carcinoma was present without an associated acinar tumor in 3 (23.1%) RPs; 2 showing tumors with large, cystic dilated glands extending into periprostatic tissue. In 7/13 cases (53.8%), the acinar component was the dominant tumor and the PIN-like carcinoma component was small (<1 cm). The overall grade at RP was GG1 (5/13, 38.5%) and GG2 (8/13, 61.5%). In all cases with an acinar component, the acinar tumor was anatomically distinct from the PIN-like carcinoma tumor. The GGs of the separate acinar tumors were GG1 (6/10) and GG2 (4/10) with percent pattern 4 ≤5% in all 4 cases. No cases were associated with metastases to lymph nodes or seminal vesicle invasion. Extraprostatic extension was present in 6/13 (46.1%) cases, from the acinar component in 1 (7.7%) case and the PIN-like carcinoma component in 5 (83.3%) cases. In all 5 cases, there was a peculiar morphology of thin papillary projections into cystic dilated PIN-like carcinoma glands. Immunohistochemical expression of ERG was positive in 1/11 (9.1%) case. 1/11 (9.1%) case showed heterogeneous loss of PTEN. Overall, PIN-like carcinoma tumors are limited in size, not advanced in stage, not associated with high-grade cancer on RP, and show low rates of Gleason pattern 4 and TMPS-ERG rearrangement. Our study supports grading classic PIN-like carcinoma as Gleason pattern 3; at the current time we recommend grading thin papillary projections of PIN-like carcinoma as pattern 4. Longer term studies will be needed to determine the clinical significance of thin papillary projections in PIN-like carcinoma.

Atypical carcinoid of the uterine cervix accompanying adenocarcinoma in situ.

CLINICAL QUESTION: A 45-year-old woman presented with painless vaginal bleeding for 2 months. A biopsy was taken from the uterine cervix, and poorly differentiated adenocarcinoma was suspected. After three cycles of neoadjuvant chemotherapy treatment, the patient underwent radical hysterectomy with bilateral salpingo-oophorectomy, and pelvic and para-aortic lymphadenectomy.Review the high quality, interactive digital Aperio slide at http://virtualacp.com/JCPCases/jclinpath-2018-205081-1/ and consider your diagnosis. WHAT IS YOUR DIAGNOSIS?: Typical carcinoid.Poorly differentiated adenocarcinoma.Atypical carcinoid.Small cell neuroendocrine carcinoma.Sex cord-stromal tumours of the uterine cervix.-The correct answer is after the discussion. DISCUSSION: Neuroendocrine tumours of the uterine cervix are a rare cancer of the female reproductive system, accounting for approximately 1% of all female cervical malignancies.1 2 In 1997, a consensus workshop suggested four types of neuroendocrine tumours of the uterine cervix: typical and atypical carcinoid tumours, small cell neuroendocrine carcinomas, and large cell carcinomas.1 Among all the categories, small cell neuroendocrine carcinomas are of the highest incidence. A PubMed search revealed that only 15 cases of atypical carcinoid tumours of the uterine cervix have been reported.3 4 Because of infrequency, the clinical and pathological features of atypical carcinoid tumours of the uterine cervix remain unknown.Atypical carcinoids are characterised by great cytological atypia, which means abundant or scanty cytoplasm and visible nucleoli with granular chromatin. Tumour cells lined up in insular, trabecular, columnar and nested organoid patterns; they are epithelioid in appearance, but can be spindled (figure 1A). Necrosis could be observed in some areas and mitotic activity is up to 10 mitotic figures/10 high-power field (figure 1B). On immunohistochemistry, atypical carcinoids are diffuse and positive for Syn, CgA and CD56 (figure 2). An electron microscopic test was done, and several neuroendocrine granules were distributed in the tumour cell plasma (figure 3).jclinpath;71/11/1030/F1F1F1Figure 1(A) Insular, trabecular and columnar patterns of tumour cells were focally observed in the deep stroma of the cervix (H&E ×200). (B) Tumour cells showed small-sized, scanty cytoplasm, enlarged and deeply stained nuclei with condensed chromatin, obvious atypia, and increased mitotic activity (H&E ×400). (C) The cervical gland has shown atypical hyperplasia and adenocarcinoma in situ (H&E ×200).jclinpath;71/11/1030/F2F2F2Figure 2Immunohistochemical study findings: (A-C) The neuroendocrine markers Syn, CgA and CD56 were diffuse with strong expression in the tumour cell plasma. (D-E) P63 and CK5/6 for the squamous cell carcinomas showed no expression. (F-G) P16 for atypical carcinoid and adenocarcinoma in situ, respectively, had strong diffuse expression. (H-I) Ki67 had low expression in both atypical carcinoid and adenocarcinoma in situ (×200).jclinpath;71/11/1030/F3F3F3Figure 3Several neuroendocrine granules were distributed in the tumour cell plasma.Neuroendocrine tumours of the uterine cervix are sometimes combined with adenocarcinoma (figure 1C); their cytological and immunohistochemical features showed the neuroendocrine and adenomatous components shared the same origin.

Prognostic considerations of the new World Health Organization classification of lung adenocarcinoma.

The 2015 World Health Organization (WHO) lung adenocarcinoma classification divides tumours into categories of indolent pre-invasive, minimally invasive and predominantly lepidic and, by examining predominant patterns of invasion, allows for further stratification into intermediate and high-grade tumours. The impact of the 2015 classification on prognosis was reviewed by a PubMed search for search terms "adenocarcinoma", "lung pathology" and "prognosis" and relevant publications reviewed. These were sorted for data on stage and survival as impacted by histological classification, and survival studies were separated into all stage versus stage 1 studies. Predictive aspects of histological classification were also examined, but molecular correlates were not. The separation of adenocarcinoma in situ and minimally invasive adenocarcinoma from invasive subtypes as distinct prognostic entities and the prognostic significance, for disease specific and overall survival for low- and high-grade categories, are discussed. The impact on stage at presentation including risk of node metastasis by histology is examined, as well as histology in relation to recurrence after surgery. Early data with regard to the value of predominant histology in the prediction of chemotherapy response will also be explored.

Hereditary diffuse gastric cancer - pathophysiology and clinical management.

Hereditary Diffuse Gastric Cancer is an autosomal dominant inherited gastric cancer syndrome caused by germline alterations in CDH1 (E-cadherin) and CTNNA1 (alpha-E-catenin) genes. Germline CDH1 alterations encompass small frameshifts, splice-site, nonsense, and missense mutations, as well as large rearrangements. Most CDH1 truncating mutations are pathogenic, and several missense CDH1 mutations have a deleterious effect on E-cadherin function. CDH1 testing should be performed in probands. Screening of at-risk individuals is indicated from the age of consent following counselling with a multidisciplinary team. In mutation-positive individuals prophylactic gastrectomy is recommended. Endoscopic surveillance is an option for those refusing/postponing gastrectomy, those with mutations of undetermined significance, and in CDH1-negative families. Ongoing research focus on the search of genetic causes other than CDH1 or CTNNA1 germline defects; assessment of the pathogenicity and penetrance of CDH1 missense mutations and identification of somatic mechanisms behind the progression from early (indolent) lesions to invasive (lethal) carcinomas.