CERVICAL CANCER SCREENING- IS LIQUID BASED CYTOLOGY BETTER THAN CONVENTIONAL PAP SMEAR?

Worldwide, cervical cancer is the second most common cause of death amongst women with cancer.  Fortunately, the incidence of cervical cancer has decreased by more than 50% in the past 30 years, largely due to the increasing use of cervical cancer screening with cervical cytology.

Although worldwide cervical cancer rates have decreased dramatically with the increase in screening efforts, incidence and prevalence in developing countries remains high due to lack of screening programs.

 

Cervical cancer screening methods

The conventional pap smear (CPS)

The mainstay of cervical cancer screening for the last 60+ years has been the Papanicolaou test. The Papanicolaou test, also known as the Pap smear, was developed in the 1940s by Georgios Papanikolaou. It involves exfoliating cells from the transformation zone of the cervix to enable examination of these cells microscopically for detection of cancerous or precancerous lesions. The cervical cells obtained is directly transfer onto a microscope slide for evaluation.

The conventional papanicolaou (Pap) test is considered suboptimal due to false-negative and false-positive test results.  This is caused by the poor quality of sampling and preparation (obscuration by blood or inflammation, bad cell fixation, and inhomogeneous distribution of cells) and by errors in detection and interpretation. All these contributed to an unsatisfactory smear and need for repeat test albeit a small incidence of 1%.

Liquid based cytology (LBC)

Liquid-based cytology was developed as an alternative to conventional pap smear. This method involves the collection of cervical cells using a traditional sampling device and rinsed into a vial with preservation solution rather than being smeared on a slide.  It is centrifuged to filter out cervical cells from other contaminants and the product is then analyzed in the cytology lab.  Because only a representative portion of the sample is used, the residual material in the vial may be used for ancillary testing such as reflex human papillomavirus (HPV) testing and other tests.

 

Is the liquid based cytology superior to CPS?

Siebers et al (JAMA 2008) had conducted a large prospective trial with 90000 women, comparing the screening performance of the two screening methods.   The results showed no differences were found in the cytological test positivity rates between methods. He concluded that liquid-based cytology was not superior to conventional Pap test regarding detection rates of histologically confirmed outcomes (gold standard). A reduced unsatisfactory rate was found when using liquid-based cytology even though the added value was limited because the unsatisfactory rates were already low. On the other hand, liquid-based cytology tests cost more money than a conventional Pap test.

The results of a systematic review and meta-analysis by Arbyn (2008), utilizing strict criteria had similarly found that liquid-based cervical cytology is neither more sensitive nor more specific for detection of high-grade cervical intraepithelial neoplasia (abnormal premalignant cervical cells) compared with the conventional Pap test.

Despite the above findings, Schiffman and Solomon (2009) observed that liquid-based cytology often results in fewer unsatisfactory specimens and allows for HPV testing on the same sample.  They also observed that liquid-based cytology has virtually replaced conventional Pap smears in the United States.  Although liquid-based cytology is more expensive, its ease of use allows laboratories to process slides more quickly and efficiently makes it the preferred method at the expense of a limited public program funding.

The bigger question, however, is how liquid based cytology screening itself will fit into the broader picture of cervical cancer prevention in low resource countries, where cervical cancer is more prevalent couple with lack of adequate screening.  Saraiya (2010) argued that findings of Siebers et al validated the practices of clinicians and laboratories that have continued to use conventional cytology.

 

Conclusions

Both conventional cytology and liquid-based cytology have been shown to have similar sensitivity and specificity for cervical dysplasia (premalignant cervical cells).  In addition, both types of cytological screening are considered acceptable by the American College of Obstetricians and Gynecologists.

 

References

Arbyn M et al., Liquid compared with conventional cervical cytology.  Obstet Gynecol (2008);111(1): 167-177

Schiffmans et al., Screening and prevention methods in cervical cancer. JAMA (2009);302(16):1809-1810

Siebers AG et al., Cytological detection of cervical abnormalities using liquid-based compared with conventional cytology .  Obstet Gynecol (2008);112(6): 1327-1334.

Suraiya et al., To the Editor: Liquid based cytology versus conventional cytology in detecting cervical cancer. JAMA(2009);303(11):1034

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LATEST ON UTERINE TRANSPLANT- A DISAPPOINTING OUTCOME FOR THE FIRST UTERINE TRANSPLANT IN U.S.

The recent achievement of successful uterine transplant by Professor Brannstrom from Europe opens up a new excitement in the field of reproductive medicine.  This new surgical technology gives hope to women with uterine factor infertility, to conceive. Currently, the European team had reported five babies born to mothers with transplanted uteruses

On February 25th, 2016, the Cleveland Clinic in United States, similarly reported its successful uterine transplant, using a uterus from deceased donor.  However, the recipient developed complications within a week.  This had led to removal of the transplanted uterus on March 8th.  The preliminary report showed that the complication was due to infection that compromised the blood supply to the newly transplanted uterus.  The US team is actively looking into improving the protocols to reduce the risk of this complication in the future.

MRI GUIDED FOCUSED ULTRASOUND (MRIGFUS)- A NOVEL APPROACH TO THE TREATMENT OF UTERINE FIBROID?

Uterine fibroid is one of the commonest benign tumor amongst women.  It is present in 30%  of premenopausal women and is the main indication for hysterectomy.  Currently, there is no effective medical treatment available.  The uterine artery ablation has been offered as alternatives to surgical treatment (hysterectomy) but its clinical application is limited.

The MRI guided focused ultrasound is a minimally invasive fibroid treatment that uses a tightly focused ultrasound waves to deliver heat that instantaneously destroys fibroid tissue.  It is performed as an outpatient procedure with sedation.  The fibroid location is identified using T2-weighted MR imaging followed by a pretreatment planning and application of multiple therapeutic sonications to a temperature of at least 65 degree Celsius.  The heat generated basically ablates the fibroid tissue. The whole procedure takes about two to three hours.  The recovery time of about one to three days appears promising as a viable alternative to the current surgical option.

There are many reports of the experience with this treatment modality.  These reports were not from a high quality study design and occasionally sponsored by industry that are prone to bias and confounding.

There is only one randomized, placebo-controlled trial (PROMISe) to date, that assess the effectiveness of MRIgFUS therapy.  This is a high quality study and has a post treatment follow-up period of 2 years duration.  The result shows there is no diffence between MRIgFUS and placebo group, in terms of symptom improvement and quality of life at 4 to 12 weeks post procedure.  However, about a third (30%) of all women who had MRIgFUS therapy opted for hysterectomy by 2 years post treatment.

In summary, the MRIgFUS treatment for uterine seems promising and avoids the need for surgery.  Currently, the available results suggest its role as a temporary alternative treatment prior to the decision for hysterectomy, at best.

Reference

PROMISe trial (Pilot Randomized trial of MRIgFUS for symptomatic fibroid) trial. Fert Steril 2016

Alternative therapies in management of leiomyomas. Fert Steril 2014

Clinical improvement and shrinkage of uterine fibroids after thermal ablation by magnetic resonance-guided focused ultrasound surgery. Ultrasound Obstet Gynecol 2007.

Clinical outcomes of focused ultrasound surgery for the treatment of uterine fibroids.  Fert Steril 2006

 

 

 

RECURRENCE OF ENDOMETRIOSIS – HOW TO PREVENT IT

Endometriosis is a common, benign gynecological disorder and a leading cause of disability in women of reproductive age, responsible for dysmenorrhea, pelvic pain and subfertility.  It is a debilitating and costly disease. Surgery is the treatment of choice for its management since the efficacy of medical treatment alone is often inadequate or of limited efficacy.  Surgical excision of lesions (conservative surgery) has been shown to both improve pain and enhance fertility. This is preferred over radical surgery because most women with endometriosis are of reproductive age.

The recurrence rate

Recent reviews had estimated the recurrence rate of endometriosis to be 21.5% at 2 years and 40-50% at 5 years (Guo SW 2009), which is more frequent than previously believed.  It seems that the recurrence rate for pain or dysmenorrhea is higher than that for the clinical recurrence as defined by presence of ovarian endometrioma on pelvic ultrasound scan.  These recurrences, which lead to repeat surgeries can further reduce fertility, exacerbate pain and complications of operation, which in turn affects quality of life, and increases social costs.

How recurrences happen?

There are two main explanations leading to the recurrence of endometriosis, namely re-growth of residue lesion and de novo lesion formation.

Vignali et al. observed that during a repeat surgery, most endometriosis recurrence occurred at the same area.  Similar observation was found in cases of ovarian endometrioma, where majority (88.7%) of the recurrences was from the previously treated ovary (Guo SW 2009). Conservative surgery is sometimes insufficient to remove these lesions completely, allowing it to re-develop after operation.  The de novo endometriosis lesion occurs via the monthly retrograde menstrual blood flow into the abdominal cavity, allowing the endometrial tissue to implant.

Prevention of Recurrence

Pain symptoms

The pain symptoms of endometriosis include non-cyclical pelvic pain (chronic pelvic pain), painful menses and intercourse. The use of oral contraceptives (OC) for a period of six month or more is found to be effective in reducing endometriosis associated pain symptom recurrence.   The continuous OC regime has an advantage over the cyclical OCs, with lower recurrence and earlier benefits (Seracchioli 2010; Vlahos 2013).  Medication should be given for at least 18-24 months as the recurrence occur rapidly when medication is stopped.

 

Ovarian endometriosis (endometrioma)

Postoperative OC conveys a protective effect against recurrence.  Again, the continuous regime has an edge over the cyclical OC regime.  This benefit is conferred as long as the woman is on OC treatment but vanished rapidly upon discontinuation (Kaori K 2015).

Recommendations

All women with endometriosis, following a conservative surgery (for pain symptoms or endometrioma), should be on medication (continuous OC) as long as possible until she is ready to conceive (Dunselman GA 2014). This will effectively reduce endometriosis recurrence and need for repeat surgery, which carries its own complications.

References

  1. Dunselman GA et al., Hum Reprod 2014
  2. Guo SW. Hum Reprod Update 2009
  3. Kaori K et al., Fert Steril 2015
  4. Seracchioli R et al., Fert Steril 2010
  5. Vlahos N et al., Fert Steril 2013
  6. Vignali M et al., J Minimal Invasive Gynecol 2005

WHAT IS ENDOMETRIAL HYPERPLASIA?

I had prolonged uterine bleeding.  My gynecologist performed an endometrial curettage (DD&C) and confirmed findings of endometrial hyperplasia.

 

Endometrial hyperplasia

Endometrial hyperplasia is a condition due to abnormal thickening of the endometrium (womb lining) because of unopposed estrogen hormone stimulation.  The commonest etiology of this condition is anovulation (failure to ovulate).

Women usually present with prolonged menstrual bleeding, which can be mild spotting to heavy menstrual flow.  These symptoms can cause personal distress and inconvenience to anemia (pallor) due to chronic blood loss.

 

Making the diagnosis

The pelvic ultrasound usually shows a thickened endometrium characterized by an echogenic endometrium.  Curettage of the endometrium provides opportunity to remove the abnormal endometrium as well as tissue assessment.  A hysteroscopy examination of the uterine cavity provides further opportunity to exclude polyps or sinister uterine growth.

The diagnosis of endometrial hyperplasia depends on the histopathology results.  The endometrium examination may reveal findings of a simple or complex hyperplasia (types of thickening based on cellular layering). This is further classified depending on the presence of atypia (abnormality of cell structure).  The final diagnosis will appear as a simple or complex hyperplasia with or without atypia. However, for purpose of uniformity, WHO (2014) has recommended the use of Endometrial Hyperplasia without atypia and Atypical Hyperplasia to describe these pathologies.

 

The concern: Endometrial hyperplasia and endometrial (womb) cancer

The presence of endometrial hyperplasia is a precursor to endometrial (womb) cancer.  However, the risk of malignant transformation is less than 5% over 20 years for endometrial hyperplasia without atypia.

On the other hand, the risk of developing endometrial cancer is highest in atypical hyperplasia. The reported cumulative risk of cancer in 4 years is 8%, which increases to 12.4 after 9 years and to 27.5% after 19 years (Lacey JV 2010).  About 43% of this atypical hyperplasia has also been associated with a concomitant endometrium cancer at time of hysterectomy (Trimble 2006).

 

Treatment options

In view of low risk of endometrial cancer in women who have endometrial hyperplasia without atypia, an option of observation alone with follow-up biopsies can be considered. The majority of these cases regress spontaneous during follow- up.  However, treatment with progestogens has a higher disease regression rate over observation alone.  Progestogen treatment is indicated in women who fail to regress following observation alone and in symptomatic women with abnormal uterine bleeding.

Progestogen can be administered orally or by injections.  The other alternative is the use of medicated IUCD. The recommended duration of treatment is 6 months and this is followed by a endometrial biopsy confirm endometrial regression.  Two negative biopsies over six months interval are required to complete the treatment.  Any vaginal bleeding should be assessed and a relapse excluded.

Surgery is rarely indicated unless the women opted for it and do not wants medical treatment.  Other indications for surgery include failure of endometrial regression following medical treatment, persistent uterine bleeding and relapse after a completed progestogen treatment.  A hysterectomy (complete removal of the womb) is the recommended surgical option.

The treatment of endometrial hyperplasia with atypia is hysterectomy.  This is due to the high likelihood of progression to endometrial cancer. For women who prefer to keep the uterus, medical treatment in the forms of progestogen or medicated IUD can be used for women who want to preserve their uterus until a later date.

 

REFERENCE

Lacey JV et al., J Clin. Oncol 2010

RCOG Greentop guideline 2016

Trimble CL et al., Cancer  2006

 

 

 

ENDOMETRIOSIS AND RISK OF OVARIAN CANCER- Can endometriosis predispose to ovarian cancer?

Endometriosis is a common gynecological disorder.  It affects up to 10% of women in the reproductive age.  The common presentations of endometriosis are menstrual or pelvic pain, ovarian cyst and difficulty to conceive.  There has been report of malignant (cancerous) transformation of endometriosis.

Ovarian cancer is the one of the deadliest gynecology cancer as most women present at later stage of the disease.  The current treatment includes pelvic clearance, removing as much tumor as possible while the residue tissues are treated with chemotherapy.  However, the 5 years survival rate for late stage ovarian cancer remains low.  This creates anxiety and concerns amongst health professionals as well as women suffering from endometriosis.

 

Endometriosis, a precursor to ovarian cancer

There are strong evidences to support that endometriosis predisposed women to the risk of developing ovarian cancer (Nezhat 2014).  The endometriosis tissue exhibits ability to ‘travel’ (spread) to distant organ.  It does not confine itself to the female reproductive organ but can metastasize to other organs in the body.  It attaches and invades the target organ and subsequent lead to end organ damage. The endometriosis itself manifests recurrence, uncontrolled cell proliferations and growth driven by estrogen hormone.

Recently, based on molecular genetic studies, ovarian cancer can be classified into two categories, namely types I and II.  The type I tumors develop gradually, less aggressive and usually confined to the ovary at diagnosis.  They comprise approximately 25% of all ovarian cancer and have better prognosis.  These type II ovarian cancers are endometrioid, clear cells and low- grade serous subtypes.

The type II tumors are more aggressive, rapid growing and demonstrate high- grade malignancy.  There is no known precursor lesions associated with type II ovarian cancers.

They seems to arise from the fimbrial epithelium and highly unstable chromosomally (Kurman 2011).

 

How high is the risk?

The exact likelihood for a malignant transformation in women with endometriosis is unknown.  It has been found that there is a 2-3 folds risk of women with endometriosis to develop a clear cell or endometrioid ovarian cancers, compared to women without endometriosis.  These tumors are from the Type I category.  The estimated relative risk (RR) are 3.59 and 1.98 respectively (Guo 2015).

With the lifetime risk of ovarian cancer estimated at 1.4% and approximately 25% of all ovarian cancers are Type I origin (clear cell and endometrioid subtypes), the lifetime risk would be 0.34% in the general population. For women with endometriosis, the odds ratio of developing ovarian cancer is about 1.5 compared to the general female population.  An odds ratio of 1.5 means that a woman with endometriosis has a life-time risk of developing an ovarian cancer of about 1.5% instead of 1% (Pearce 2012).

The risk factors associate with malignant transformation include, women with long- standing history of endometriosis, endometriosis diagnosed at an early age, endometriosis associated with infertility, ovarian endometrioma and atypical endometriosis.

 

Final message

Endometriosis, a seemingly benign gynecological condition has shown to be associated with ovarian cancer.  However, most women with endometriosis do not develop ovarian cancer as the risk of malignant transformation remains low.  The manifest tumors are also less aggressive.

 

Notes:

Odd s ratio is the odds that an outcome (ovarian cancer) will occur given a particular exposure (endometriosis), compared to the odds of the outcome occurring in the absence of that exposure (without endometriosis).

Relative risk describes the probability of developing a disease (ovarian cancer) in the exposed (endometriosis) to the non- exposed group (non-endometriosis)

 

Reference:

  1. Pearce CL et al. Lancet Oncology 2011.
  2. Guo SW et al., Fert Steril 2015
  3. Kurman RJ et al., Hum Pathol 2011
  4. Nezhat FR et al., Int J Gynecol Cancer 2014
  5. Nezhat F et al., Fert Steril 2014

UTERINE TRANSPLANT – A PAGE FROM SCI FI.

The transplant medicine is not new – we have heard of kidney and liver transplant as common procedures. However, I was excited by the report of a successful pregnancy following a uterine (womb) transplant.

A uterine transplant is the surgical procedure whereby a healthy womb from a donor is transplanted to a recipient who was born without a womb or had womb removed in cancer surgery.

The uterus allow a normal reproduction process whereby the fertiled egg implant and grow into a fetus. This uterine transplant is a potential treatment for women with no uterus.

The first successful uterine transplant was performed in Turkey in 2011 for a women who had been born without the uterus. She managed to conceive in 2013 but had a miscarriage at 8 week gestation.

This success was followed by a more ambitious project undertaken by Professor Brannstrom and team at the University of Gothenburg, Sweden. The team performed uterine transplant on nine women. Only seven of them proceeded to embryo transfer following an IVF treatment. In 2014, they reported the first livebirth from a uterine transplant recipient, by caesarean section at 32 weeks. The baby weighed 1.7kg at birth.

The transplanted uterus is intended to be temporary and will be removed once successful pregnancies are completed. This is to avoid the need for long term immunosuppressant treatment. Immunosuppresant drugs are used in transplant medicine to avoiud graft rejection.

Currently this procedure remains experimental and is expensive. However, this successful pregnancy outcome is yet another major medical milestone in reproductive medicine.