Could modified PapTest help detect endometrial and ovarian malignancy?

A new multiplex PCR-based test called PapSEEK was able to detect endometrial and ovarian malignancy from fluid samples collected during routine Pap test, reported Yuxuan Wang, MD, of Johns Hopkins University School of Medicine in Baltimore.

The authors also used a longer sampling brush that sweeps cells from the lining of the uterus called Tao brush, to further increase the sensitivity of detection for the less accessible tumors.

The paper was published in Journal Science Translational Medicine on March 21, 2018, and the study identified endometrial cancer with high sensitivity from samples collected by Pap test and Tao brush, while sensitivity for reporting ovarian cancer was low, but increased when it was combined with DNA testing in the blood samples.

Pap test has been instrumental in bringing down the incidence of cervical cancer by about 60% since its introduction in 1940 but it is not able to detect endometrial and cervical cancers. The researchers at John Hopkins University based this test on the evidence put forth by the previous study published in Journal Science Translational Medicine that both endometrial cancer and ovarian cancer shed cells that collect at the cervix. These cells can be identified by looking for ‘Tumor DNA’ in the samples.

It is to be noted that DNA mutations have already been identified for specific cancers. In the study, the researchers tested for 18 genes common to endometrial and cervical cancer.

The researchers looked at 1915 samples from 1658 individuals, including 656 patients with endometrial or ovarian cancers and 1002 healthy controls.

PapSEEK was used on Pap test samples of 382 women with endometrial cancer, 245 women with ovarian cancer, and 714 women without cancer.

PapSEEK gave a positive result in 81% of endometrial cancer patients, which included 78% of patients with stage I or stage II disease, and 92% of patients with stage III or stage IV disease.

While 33% of Pap test samples were PapSEEK-positive in ovarian cancer patients, including 34% of patients with stage I or stage II disease and 33% of patients with stage III or stage IV disease.

When samples collected by Tao brush was examined, they tested positive in 93% of cases endometrial cancer and 45% cases of ovarian cancer.

The researchers then tested plasma samples from 83 ovarian cancer patients and found that 43% of these patients had detectable circulating tumor DNA. On applying the papSEEK test to the Pap test samples from this group, it was seen that positive results were obtained in 63% of patients.

Currently, there are no screening tests for both endometrial and ovarian cancer and incidence of both is on the rise.  

More than 63,000 women are diagnosed with endometrial cancer in the U.S. each year, and more than 11,000 die each year from the disease. Ovarian cancer is less common but more lethal, affecting more than 22,000 women and killing about 14,000 in the U.S. each year.

Yuxuan Wang, first author on the study said, “Our study demonstrates the ability to detect endometrial and ovarian cancer using cervical fluids obtained using two different methods.”

Full text

Media Courtesy: John Hopkins University 

News from NAMS 2017: Postmenopausal bleeding is always a red flag, unless proven benign

Every postmenopausal bleeding mandates a complete and systematic investigation to rule out endometrial malignancy and blind biopsies are no longer the norm, according to a presentation by Steven R. Goldstein, MD, a professor of obstetrics and gynecology at New York University School of Medicine, New York City here at the North American Menopause Society (NAMS) 2017 Annual Meeting.

“If you’re postmenopausal and not on hormone therapy or tamoxifen, you shouldn’t be bleeding,” he further added.

American Cancer Society estimates that in year 2017, about 61,380 new cases of endometrial cancer and uterine sarcoma will be diagnosed and about 10,920 women will die from these cancers. The average age at diagnosis is 60 and postmenopausal bleeding is the most common presentation in nearly all the cases.

In majority of women who present with postmenopausal bleeding, the cause is atrophic changes of endometrium or vagina, but depending upon other risk factors, 1-14% of these women will harbor a malignancy and it is important not to miss these women.

ACOG advocates endometrial evaluation in any women presenting with abnormal uterine bleeding (AUB), but blind biopsy is no longer sufficient in ruling out uterine malignancy.

Blind biopsy alone could miss the diagnosis of focal lesions in up to 18% of patients
Endosee

Dr Goldstein said, “The standard of care has changed. Now the standard of care corroborates that a negative blind biopsy is not a stopping point. Clinicians can still begin with a blind biopsy, but unless it is malignant or complex atypical hyperplasia, the endometrial evaluation is not complete."

If cancers occupy less than 50% of the surface area of the uterine cavity, it can very much be missed with a blind biopsy.

if cancer occupies less than 50%, of the surface area of the endometrial cavity, the cancer can be missed by a blind biopsy
Endosee

The Evaluation Algorithm

The investigation should ideally begin with transvaginal ultrasonography(TVS), or sonomicroscopy, to determine the thickness of the endometrium. If distinct endometrial echo or lining, less than or equal to 4 mm is visualized, no further endometrial sampling is required. (99.8%- 100% negative predictive value)

But, in many patients it is not possible to see the endometrial lining because of obesity, adenomyosis structural nonalignment or fibroids.  So, if the endometrial thickness is more than 4 mm or the endometrial echo is difficult to visualize, the next logical step is to perform a sonohysterography or hysteroscopy.

By infusing fluid, clinicians can delineate clearly whether the thickening is focal or global throughout the cavity. If the thickness is global, go for a biopsy. If it is focal occupying more than 20-30% of uterine cavity, plan for a biopsy under hysteroscopic guidance.

It’s easy and timesaving to perform office hysteroscopy, with US FDA approved disposable hysteroscope called Endosee (Cooper Surgical). It provides a quick point of care option and does not require sterilization or special storage. Physicians can take a biopsy under direct vision and resolve the dilemma.

If the patient’s first point of contact is not an obgyn but a primary care physician, an internist or physician from some other specialty, they should at least order a TVS, so that by the time the patient is seen by a gynecologist, the initial sonography report is ready.

NAMS press release

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New study reassures postmenopausal women about safety of vaginal estrogen.

Postmenopausal women using vaginal estrogen are not at increased risk of cardiovascular disease and cancer reports the result of study published August 14, 2017 in Menopause.

This is another important study conducted using data from Women's Health Initiative(WHI) observational study which tracked the medical history and health habits of 93,676 women nationwide for 8-12 years. The current study recruited 45,663 women between 50-79 years of age, across 40 US clinical centers. These women did not use systematic estrogen and underwent a median follow-up of 7.2 years.

Results of this prospective observational cohort study showed that in women with intact uterus and using vaginal estrogen, the risk of cardiovascular event, pulmonary embolism, stroke, invasive breast cancer, endometrial and colorectal cancer does not exceed the risk faced by non-hormone users.

Women using vaginal estrogen had 32% lower risk of global index event (GIE), defined as time to first occurrence of coronary heart disease (CHD), invasive breast cancer, stroke, pulmonary embolism, hip fracture, colorectal cancer, endometrial cancer, or death from any cause as compared to non-users (GIE adjusted hazard ratio 0.68, 95% confidence interval 0.55-0.86).

Surprisingly, in Hysterectomized women the composite risk of GIE or individual event did not differ much among users and non-users (GIE adjusted hazard ratio 0.94, 95% confidence interval 0.70-1.26).

Based on the results of this trial, US FDA is considering a proposal to revise the warning labels on low dose estrogen packaging to incorporate the safety profile of vaginal estrogen.

Current labels were approved before any evidence was put forth about safety of vaginal estrogen and it may discourage patients from using topical estrogen which are safe and highly effective in treatment of genitourinary symptoms of menopause. 

Different formulations like topical creams, an intravaginal insert, and an intravaginal ring have the same safety and efficacy.

JoAnn Pinkerton, MD, executive director, North American Menopause Society (NAMS), said in a  position statement released by North American Menopause Society on August 17, “These findings should reassure women and their healthcare providers that low-dose vaginal estrogen, which keeps blood levels within the normal postmenopausal range, is effective and safe for postmenopausal women who need relief from only vaginal symptoms,” says Dr. JoAnn Pinkerton, NAMS executive director. “The boxed warnings about the risk of heart disease, stroke, blood clots, and cancer do not apply to these low-dose vaginal therapies. Instead, women who experience bleeding or those with breast cancer should include their healthcare providers and oncologists in deciding about this option.”

Access the Abstract, NAMS position statement.

Adjunct Metformin helps reversal of atypical endometrial hyperplasia

Adjunct metformin treatment help reversal of atypical endometrial hyperplasia (AEH) and improves overall survival in endometrial cancer reports the result of a systematic review and meta-analysis published ahead of print in Journal of Gynecologic Oncology.

Metformin is named as ‘Magic Bullet’ by some researchers because of its new-found role in reversing aging to improving survival in many cancers, besides being in use as antidiabetic and cardioprotective drug since nearly 60 years.

Metformin was introduced for use as antidiabetic in UK in 1958.

Endometrial cancer (EC) is one of the most common gynecological cancer. The American Cancer Society estimates that about 61,380 new cases of EC of the uterus (uterine body or corpus) will be diagnosed in 2017 and about 10,920 women will succumb to the disease.

This systematic review and meta-analysis searched Cochrane, LILACS, PubMed, Scopus and Web of Science in January 2017 and included 19 eligible studies that included information about reversal of atypical endometrial hyperplasia, cellular proliferation biomarkers expression and overall survival in metformin-users compared to non-users.

In 5 studies, metformin led to reversion of AEH to a normal histology and decreased cell proliferation biomarkers staining, from 51.94% to 34.47%.

Patients on adjunct metformin had 18% increased odds of survival as compared to patients who were not diabetic and not on metformin. (HR = 0.82; CI: 0.70–0.95; p = 0.09, I2 = 40%).

Type 2 diabetes mellitus and insulin resistance is involved in the etiology of endometrial cancer (EC), so metformin may have both direct and indirect effect on tumor regression.

There was considerable heterogenicity observed between the studies but, despite that metformin was shown to be beneficial in reversal of AEH and improving overall survival in EC.

The authors call  upon future need of prospective trials regarding the anticancer effect of metformin and improving the clinical outcomes in EC.  

Primary source: Effects of metformin on endometrial cancer: Systematic review and meta-analysis

Meireles, Cinthia G. et al.

Gynecologic Oncology , Volume 0 , Issue 0 ,

North American Menopause Society (NAMS) video series about important midlife health topics: April 2017.

The North American Menopause Society (NAMS) has started comprehensive video series for clinicians about important midlife health topics. All the interviews in the series are hosted by NAMS Board of Trustees Member and President Dr. Marla Shapiro, a Canadian physician, who led this exciting initiative.

In this monthly series, the latest video is “treatment for perimenopause and postmenopausal bleeding” Dr. Goldstein discusses what action must be taken for spotting, staining, or bleeding for perimenopausal and postmenopausal women.

                             Dr Steven Goldstein discusses treatment for bleeding.

Mayo Clinic Tampon Test for detecting Endometrial Cancer at early stage.

Image Source/Corbis

Endometrial cancer is the fourth most common cancer in women. Approximately 2.8 percent of women will be diagnosed with endometrial cancer at some point during their lifetime, based on 2011-2013 data. Most cases of endometrial cancer are diagnosed in women aged 45-74. The number of new cases of endometrial cancer was 25.4 per 100,000 women per year based on 2009-2013 cases.[1]

There is no standard screening test to identify endometrial cancer, hence it is often detected late when the disease has already advanced.

Mayo clinic expert Jamie N. Bakkum-Gamez, M.D. and her team are in the process of developing a simple screening test that can be done at home using a tampon. It is based on the concept of detecting tumor DNA hypermethylation in vaginal pool DNA picked up by ordinary tampon.

Methylation is a kind of molecular marker of cancer, and the researchers found it in 9 of 12 genes they analyzed in the cancerous women. Importantly, the tampon findings were in line with results from “endometrial brushing,” which is an invasive procedure.

 “Unfortunately, there is no equivalent to a Pap smear or a mammogram for endometrial cancer,” says Jamie Bakkum-Gamez, M.D., a gynecologic oncologist at Mayo Clinic and lead author of the study. “We know that the earlier a woman is diagnosed, the better the likelihood is that she is going to have a positive outcome from cancer treatment.

The team is carrying out larger clinical trials before the test can be turned into ‘a home-based test.’

In this Mayo Clinic Minute, reporter Vivien Williams talks to Dr. Bakkum-Gamez about the tampon test for endometrial cancer.

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[1] http://seer.cancer.gov/statfacts/html/corp.html

Oral contraceptive pill use protects against colorectal, endometrial and ovarian cancer.

 courtesy: Getty images

Women who have ever used the ‘pill’ have a decreased chance of having colorectal cancer, endometrial cancer or ovarian cancer than women who had never used the pill according to a new research from The University of Aberdeen, UK

The study was published in February issue of American Journal of Obstetrics and Gynecology.[1]

The study answers three important questions about safety of the use of OC. (1) What is the duration of benefits for endometrial, ovarian, and colorectal cancer. (2) Does combined oral contraceptive use during the reproductive years led to new cancer risks as we age? (3) What is the risk benefit ratio for cancer among past users as they age and enter old age when the general population risk of cancer increases?[2]

This is the longest running study of its kind  that looked at data from 46,022 women who were recruited by the UK Royal College of General Practitioners' Oral Contraception Study in 1968 -1969 and were followed for up to 44 years. The study looked at risk of specific and general cancer risk for women who have ‘ever’ used the pill against the women who have ‘never’ used the pill.

The pill was first approved for contraceptive use in 1960 and was an instant hit with 2.3 million women using it by 1963. Controversies ranged from its inception and are still rife about the pill causing cancers, blood clots, heart attack and stroke.

Few studies have documented that women are protected against GI malignancies and are at increased risk of breast and cervical cancer while currently using pills or being a recent user.

The current study data showed that the protective effect of pill lasts for 30 years even after the pill is stopped and pill users have a 19% lower risk of GI malignancies, 26% lower chance of lymphatic, and hematopoietic cancer, 34% lower risk of endometrial cancer and a 33% lower risk of ovarian cancer.

The study showed a slight increased chance of breast and cervical cancer while using the pill but this was neutralized and plummeted to the general population risk in 5 years of stopping the pill.

The cohort did not show increased risk of any other malignancy as the women aged.

The authors concluded that “Most women who choose to use oral contraceptives do not expose themselves to long-term cancer harms; instead, with some cancers, many women benefit from important reductions of risk that persist for many years after stopping.”

Professor Helen Stokes-Lampard, Chair of the RCGP, said: “Millions of women worldwide who use the combined oral contraceptive pill should be reassured by this comprehensive research that they are not at increased risk of cancer as a result – and that taking the pill might actually decrease their risk of certain cancers.”[3]

“This is not to advocate that women should be given the pill as a preventative measure against cancer as we know that a minority of women do have adverse health effects as a result of taking the pill. Ultimately decisions to prescribe the pill need to be made on a patient by patient basis, but this research will be useful to inform the conversations we have with our patients when discussing various contraceptive options that are available.”

“Long-term and ongoing research into the health effects of any medication is important in shaping new clinical guidelines around the care we are able to provide to our patients – and it’s encouraging to hear that RCGP research that originated in in the 1960s is still having a positive impact and increasing our knowledge now.”

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[1] Iversen L, Sivasubramaniam S, Lee AJ, et al. Lifetime cancer risk and combined oral contraceptives: the Royal College of General Practitioners’ Oral Contraception Study. Am J Obstet Gynecol 2017

[2] http://www.sciencedirect.com/science/article/pii/S0002937817301795

[3] http://www.rcgp.org.uk/news/2017/march/pill-study-should-reassure-millions-of-women-workdwide-says-rcgp.aspx

Value of hormonal treatment in endometrial hyperplasia debated— News from ACOG Annual Clinical and Scientific Meeting 2016.

The John I. Brewer Memorial Lecture on Day 2 of the Annual Clinical and Scientific meeting, ACOG  2016 considered the role of hormones in treatment of Endometrial Hyperplasia vs the common surgery of Hysterectomy.

Debaters were David E. Cohn, MD, professor in the Department of Obstetrics and Gynecology and director of the Division of Gynecologic Oncology at The Ohio State University College of Medicine, and Amanda Nickles Fader, MD, associate professor and director, The Kelly Gynecologic Oncology Service and Johns Hopkins Hospital in Baltimore. They all agreed that when treatment is tailored according to patient need both forms can be beneficial.

Dr. Cohn opined that in patients who are fit for surgery and have completed the family the most effective and definitive way of preventing the transition into endometrial cancer is hysterectomy. He cited the 2006 prospective cohort study in which out of 289 women with atypical endometrial hyperplasia on biopsy or curettage,42.6 percent had endometrial cancer at hysterectomy within 12 weeks of sampling. He also said that hormonal treatment has to be continued for an indefinite period of time vs hysterectomy which is a one-step procedure with much higher success rates.

He also referred to a meta-analysis of 34 observational studies in which progestins were used to treat atypical endometrial hyperplasia. The statistical analysis showed that while 86% of women saw regression, 3.6% of women had ovarian cancer and 1.9% had advanced endometrial cancer.

He further quoted “That’s sobering news about the potential for bad outcomes with progestins.”

He acknowledged the committee opinion from 2015 that says “Progestin treatment was an unproven but commonly used alternative to hysterectomy, but optimal doses and duration of treatment need to be defined and post-hormonal surveillance and frequency is yet to be determined. It is also not determined whether it should be continuous or cyclical. And also lacks the optimal clinical as well as histological measures of response.”

He concluded by seconding the ACOG committee opinion of lots of unanswered questions regarding the use of progestins therapy.

The second debater Dr. Fader argued in favor of progestins therapy and stressed that the surgical option is chosen more out of fear than by evidence, nonetheless ample evidence exists in support of hormonal treatment.

As times have changed in last 15 years and in contemporary times, a number of organ-sparing treatments have become a reality. She further said “Almost all endometrial hyperplasia is sensitive to hormonal treatment and most — including atypical hyperplasia — regresses or remains unchanged without therapy and doesn’t progress to cancer.”

She presented evidence in the form of results of 150 retrospective studies and 12 prospective, in which progestin treatment brings about atypical hyperplasia regression in 75 to 95 percent of cases. 

Additional review of 4 large studies also showed that progestins were associated with regression of hyperplasia due to unopposed estrogens in 90% of patients.

Dr. Fader also said that with 40% of endometrial hyperplasia patients are obese or want to retain fertility, making hormonal treatment a valid choice for them. Endometrial hyperplasia is a public health problem due to increasing demographics of obesity and endogenous estrogen production, with many of the women younger than 45 years of age, which increases the need of exploring life style modifications and treatment beyond surgery a viable option.

Both the debaters agreed upon the impact of obesity on endometrial hyperplasia and the Dr.Cohn pointed out that early data on  bariatric surgery is promising in converting abnormal endometrium into normal endometrium without surgery. 

References:

http://www.acog.org/-/media/Committee-Opinions/Committee-on-Gynecologic-Practice/co631.pdf?dmc=1&ts=20150426T1515499455

http://www.acogdailynews.com/role-of-hormones-in-endometrial-hyperplasia-debated/

Endometrial cancer management guidelines updated: assorting the uncertainties! -----3

The first joint European Society for Medical Oncology (ESMO), European SocieTy for Radiotherapy & Oncology (ESTRO) and European Society of Gynaecological Oncology (ESGO) consensus conference on endometrial cancer was held on 11–13 December 2014 in Milan, Italy.

These guidelines were published in an article by Colombo N et al in January issue of Annals of Oncology. 

These guidelines were developed based on 12 questions identified by the expert panel.

The earlier 2 questions were answered in previous parts.

The third question is: Which (molecular) Markers Can Help Distinguish (pre)Cancerous Lesions from Benign Mimics?

 

Differential diagnosis between benign uterine lesions and endometrial (pre)carcinomas is based mainly on morphological criteria but may be supported by additional immunohistochemical (IHC) markers and molecular alterations in problematic cases.

Currently, AH/EIN is the preferred terminology of the precursor lesion of the most common type of endometrial carcinoma, endometrioid carcinoma, including its variants.

Recommendation 3.1: In case of uncertainty low threshold referral to a specialised gynaecopathologist is recommended.Level of evidence: V,Strength of recommendation:A.


Recommendation 3.2: PTEN and PAX-2 IHC is recommended to distinguish AH/EIN from benign mimics. Other markers that can be used in this context are MLH1 and ARID1a by IHC.Level of evidence: IV,Strength of recommendation: B


Recommendation 3.3: IHC is not recommended to distinguish APA from AH/EIN.Level of evidence: V,Strength of recommendation: B


Recommendation 3.4: p53 by IHC is recommended to distinguish serous endometrial intraepithelial carcinoma (SEIC) from its mimics.Level of evidence: IV,Strength of recommendation: A


Recommendation 3.5: A panel of markers must be used in cases where endocervical cancer is suspected. This panel should include at least ER, vimentin, CEA and p16 by IHC, and needs to be assessed in the histologic and clinical context. In addition, HPV analysis can be considered.Level of evidence: IV,Strength of recommendation: B


Recommendation 3.6: WT-1 by IHC is the recommended marker to determine the origin of serous cancer.Level of evidence: IV,Strength of recommendation: A



Recommendation 3.7: Morphology (and not IHC) should be used to distinguish AH/EIN from EEC.Level of evidence: IV,Strength of recommendation: A


To be continued…..

References:

Colombo N,Creutzberg CL, Amant F et al. ESMO-ESGO-ESTRO consensus conference on endometrial cancer: diagnosis, treatment and follow-up. Ann Oncol 2016; 27: 16–41.