Hospital Medicine

Cervical cancer

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Cervical cancer

I. What every physician needs to know.

With nearly 500,000 new cases diagnosed annually, cervical cancer is the third most common cancer diagnosed worldwide and accounts for over 200,000 deaths from cancer in women, the second most common cause of cancer-related mortality. More than 80% of these cases occur in developing countries where widespread screening for cervical cancer has not been implemented.

Cervical cancer screening using the Papanicolaou (Pap) smear began in the mid-twentieth century Xin the United States (US); at the time, cervical cancer was the number one cause of cancer-related deaths in women. However, with routine screening with Pap smears for women, the incidence of the disease has dropped dramatically. The American Cancer Society estimates that 12,900 women were diagnosed with Invasive Cervical Cancer (ICC) in 2014, and 4100 of them will die.

Racial and ethnic disparities still exist with cervical cancer, with Black and Hispanic women having higher incidence rates, as well as being diagnosed at later stages of the disease as compared to women of other races and ethnicities. This is likely related to decreased access to Pap smear testing and/or decreased rates of follow-up for treatment.

The natural history of cervical cancer is well known and involves a continuum of cellular changes from well differentiated low-grade lesions, to poorly differentiated high-grade lesions, to cellular intraepithelial neoplasia, and finally invasive cancer.

Diagnosis and definitive treatment at any of the preinvasive stages can prevent progression to more invasive, advanced stages. The causative agent for cellular changes, dysplasia, and eventual cancer has been identified as human papilloma virus (HPV), of which there are over 100 different types, both low- and high-risk. The most common types associated with cervical cancer are HPV 16 and 18, which together account for over 70% of cervical cancer cases.

II. Diagnostic Confirmation: Are you sure your patient has cervical cancer?

Because of widespread use of the PAP smear, cervical cellular abnormalities are typically first identified on cytology. Abnormalities identified from the Pap smear that are suspicious of cancer require further diagnostic work-up and confirmation via cervical biopsy.

Using a colposcope, which serves to light and magnify the cervix, directed biopsy samples are taken of any tissue that appears abnormal. Acetic acid turns cells with increased nuclear density white, helping to identify suspicious areas for biopsy. If cancerous cells are present, the cervical pathologist will confirm the diagnosis of cervical cancer.

A. History Part I: Pattern Recognition:

Unfortunately, cervical cancer does not present with symptoms until late in the disease. As the tumor grows large and bulky within the pelvic cavity, it can become friable and easily bleed. Women may then report abnormal vaginal discharge or bleeding after sex.

B. History Part 2: Prevalence:

With nearly all cervical cancers being caused by HPV, risk factors for cervical cancer involve risk for exposure and persistent infection with the human papilloma virus. Sexually transmitted, risk for exposure to HPV is similar to other sexually transmitted infections - multiple sexual partners, having a partner engaged in high-risk behavior and absence of barrier protection during intercourse. However, HPV exposure is very common - most women will be exposed to it at some point in their lives and clear the infection with their immune system.

Over 28% of women are infected with HPV within one year of first sexual intercourse and the incidence increases to almost 50% by 3 years with exposure to a single, first partner. This risk is increased when the first male partner is sexually experienced. The vast majority of these infections will be cleared by the body's own immune system, with nearly half of new infections being undetectable within 6-12 months, and 90% clearing within a few years after initial infection. The rate of clearance is high within the first few months after infection, but declines over time.

HPV 16 is identified as the most oncogenic type, found in 53% of cervical cancer cases. Even when a carcinogenic HPV is detected within cervical epithelium by HPV testing, a concurrent cervical abnormality is only detected 25-33% of the time. For the low number of HPV infections (5%) that persist for more than a few years, nearly 40% will go on to develop into high-risk lesions (CIN3) making persistent infection with a high risk HPV type the most significant factor for neoplastic transformation. CIN3 lesions then grow slowly over time before invading the epithelial basement membrane and becoming invasive cervical cancer (ICC), with the greatest predictor for rapidity of invasion being infection with HPV type 16.

Risks for persistent exposure that can then lead to cervical dysplasia and eventual cancer include being under the age of 16 at first exposure (immature squamocolumnar junction that is more susceptible to infection), infection in post-menopausal state, tobacco use, long term use of oral contraceptives (estrogen and progesterone stimulate transcription and cell proliferation), multiparity, and coinfection with human immunodeficiency virus (HIV) or other reason for immunosuppression.

C. History Part 3: Competing diagnoses that can mimic cervical cancer.

The differential diagnosis for cervical cancer if presenting with symptoms of vaginal bleeding includes pregnancy and pregnancy related conditions (e.g. missed abortion, ectopic pregnancy, placenta previa), medications and iatrogenic causes (anticoagulants, antipsychotics, corticosteroids, intrauterine devices, hormonal contraception or hormonal replacement), or systemic conditions (coagulopathies, PCOS, renal disease, thyroid disease).

If presenting with discharge or bleeding, other possibilities to consider would be genital tract pathology including infection with a sexually transmitted infection, neoplasia of the uterus, uterine leiomyomata polyps of the cervix or endometrium, or trauma. However, once a biopsy is taken, a definitive diagnosis of cervical cancer can be made.

D. Physical Examination Findings.

In patients with early-stage cervical cancer, physical findings are usually lacking. As the disease progresses, you may see visible abnormalities, including ulceration, mass lesions or erosions on the cervix, along with inguinal lymphadenopathy.

Eventually these abnormalities can extend into the vaginal cavity. With local invasion, there may be rectal lesions and/or bleeding from the rectum. Compression of the iliac vein by the increasing tumor burden and invasion of the lymphatic system can lead to lower extremity swelling and edema.

E. What diagnostic tests should be performed?

The Pap smear is the definitive test in the screening for precursor lesions of the cervical epithelium. Abnormalities identified on cervical cytology with the Pap smear are then confirmed with a biopsy. Consensus screening guidelines updated in 2012 are as follows:

  • Cervical cancer screening should begin at age 21

    • Regardless of age of sexual debut

  • Women 21-29 should be screened with cytology alone every 3 years

    • HPV testing should not be used as a component of co-testing or as a primary stand-alone screen in this age group

  • For women ages 30-64, cytology and HPV testing (co-testing) every 5 years is the preferred screening method

    • Cytology alone every 3 years is acceptable if HPV testing unavailable

  • Stop screening at age 65 for women with adequate negative prior screening and no CIN2+ in the last 20 years

    • Adequate negative screening is 3 consecutive negative pap smears or 2 consecutive negative co-tests within the last 10 years, most recent within the last 5 years

    • Do not resume if the woman reports having a new sexual partner

  • Stop screening after hysterectomy with removal of the cervix and no history of CIN2+

If initial screening results require further diagnostic testing, the patient undergoes colposcopy allowing for directed biopsies. The patient is placed in the dorsal lithotomy position and a speculum is inserted into the vagina to expose the cervix, which is then painted with iodine and/or acetic acid solution to illuminate abnormal areas. Visualization of the transformation zone (site where precancerous changes begin) is critical for a complete examination. Areas with a high nuclear density will turn white with the application of acetic acid; in addition, areas of high vascularity can be visualized through the colposcope. These areas are considered for biopsy, and then sent to the pathologist for review and diagnosis.

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

As noted, the Pap smear is the screening test used in the US to evaluate for cervical abnormalities in the pre-invasive stage. The sensitivity of a single Pap smear for identifying CIN 2 or a higher-grade lesion ranges from 55-80%%, and thus many true positives may be missed. The specificity of the Pap test for identifying CIN2 or a higher-grade lesion is about 85%. Co-testing raises the sensitivity for detecting CIN2, CIN3, or cancer to above 95%, with a corresponding loss of specificity to less than 75%.

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Imaging is not required to help in the diagnosis of cervical cancer. Once diagnosed, imaging studies such as chest x-ray, renal ultrasonography, abdominal/pelvic magnetic resonance imaging (MRI), and increasingly Positron Emission Tomography (PET)/computed tomography (CT) scan are used for staging.

F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.

N/A

III. Default Management.

Cervical cancer is a slow-growing disease that develops over 15-20 years from initial HPV infection and cervical abnormalities. There are several steps along the path where interventions can prevent the progression to cancer.

For patients who are HPV-positive with negative cytology on screening, repeat co-testing at one year is acceptable. Alternatively, HPV DNA typing can be done, and if it is positive for high risk (HR) HPV (types 16 or 18), colposcopy is indicated.

Patients with initial screening results of atypical squamous cells, undetermined significance (ASC-US) and HPV positive co-testing; atypical squamous cells–cannot exclude high-grade squamous intraepithelial lesion (ASC-H); low-grade squamous intraepithelial lesion (LSIL) without HPV co-testing or HPV positive co-testing; or high-grade squamous intraepithelial lesion (HSIL) should be referred for colposcopy.

If biopsy results reveal CIN I and original cytology demonstrated ASC-H or HSIL, follow-up with co-testing at 12 months and 24 months is recommended. Alternatively a diagnostic excision procedure can be performed. This closer follow-up is warranted because 84 to 97% of these women will have at least CIN 2 on excision.

CIN3 is considered a cancer precursor. About 12% of cases of CIN 3 progress to invasive cancer, 33% regress and the rest remain CIN3. For women with CIN2 or CIN3 and satisfactory colposcopy, ablation of the T-zone or diagnostic excision is recommended.

Once invasion of the basement membrane has occurred, an invasive cervical cancer diagnosis is made. Treatment is then dependent on the tumor size and extension. While the tumor is confined to the uterus, depending on the age of the patient and desire for future childbearing, a conization, where a significant portion of the cervix that the tumor is confined to is removed, or a complete hysterectomy is performed.

As the tumor progresses to higher grades, pelvic lymphadenectomy, external pelvic radiation, brachytherapy, and chemotherapy are added to the treatment armamentarium.

A. Immediate management.

As noted above, cervical cancer develops over decades and does not present as an emergency.

B. Physical Examination Tips to Guide Management.

N/A

C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.

Women who remain HPV-positive after treatment for CIN2 and CIN3 are at increased risk of recurrent or residual CIN. HPV-negative women rarely have recurrent or residual lesions- negative predictive value (NPV) of 98%. This is higher than the NPV of negative resection margins (91%) or cervical cytology (93%). Therefore HPV testing may be used to monitor post-treatment status. Cytology alone or combined with colposcopy at 6-month intervals is also an option. For women treated for CIN2 and/or CIN3, co-testing at 12 and 24 months is recommended. If both are negative, repeat in 3 years, then return to routine screening for at least 20 years.

If cervical cancer is diagnosed, optimal follow-up has not been established. Gynecologic examination including a Pap smear every 3 months for the first 2 years, every 6 months for the next 3 years and yearly thereafter has been recommended.

D. Long-term management.

Patients should continue to have annual Pap smears with early intervention with colposcopy for any cytologic abnormalities after being treated for cervical cancer.

E. Common Pitfalls and Side-Effects of Management

N/A

IV. Management with Co-Morbidities

Because dosing of chemotherapy and coordination of radiotherapy is carried out by the gynecologic oncologist, radiation oncologist and gynecologist, the hospitalist will not have to alter management for the patient with renal insufficiency, liver insufficiency, heart failure, or other medical comorbidities.

A. Renal Insufficiency.

No change in standard management.

B. Liver Insufficiency.

No change in standard management.

C. Systolic and Diastolic Heart Failure

No change in standard management.

D. Coronary Artery Disease or Peripheral Vascular Disease

No change in standard management.

E. Diabetes or other Endocrine issues

No change in standard management.

F. Malignancy

No change in standard management.

G. Immunosuppression (HIV, chronic steroids, etc.)

Patients with pre-invasive lesions with comorbid HIV should be aggressively managed if HPV positive with cytologic abnormalities because of the increased risk of persistent infection with decreased immunologic function for clearance.

ICC in an HIV-positive woman is an acquired immune deficiency syndrome (AIDS) defining neoplasm as of 1993. There is an 8.8 times higher incidence of ICC in HIV positive women than HIV negative women. ICC tends to be more advanced at diagnosis with a higher 24-month mortality and is more likely to persist or recur in HIV-infected women.

Studies suggest that the diagnosis of ICC in HIV-positive women is unrelated to CD4 count or effective antiretroviral therapy. Screening Pap smear with HPV co-testing should be performed at initial diagnosis of HIV and 6 months later; if both are negative, yearly screening with co-testing is recommended, different from the less frequent guidelines recommended for HIV negative patients which endorses every 3-5 year screening.

There is a low threshold for colposcopy in HIV-positive women with abnormal Pap cytology. Any atypia such as ASC-US or atypical glandular cells of undetermined significance (AG-US) or higher changes should be referred. The entire genital tract (cervix, vagina, vulva, and perianal area) should be evaluated at the time of colposcopy because multifocal disease is a common problem among HIV-infected women. HIV-positive women with a history of hysterectomy and any history of abnormal Pap smear should continue to receive yearly Pap smears due to the higher incidence of extra-cervical disease.

H. Primary Lung Disease (COPD, Asthma, ILD)

No change in standard management.

I. Gastrointestinal or Nutrition Issues

No change in standard management.

J. Hematologic or Coagulation Issues

No change in standard management.

K. Dementia or Psychiatric Illness/Treatment

No change in standard management.

V. Transitions of Care

A. Sign-out considerations While Hospitalized.

Patients hospitalized with cervical cancer are usually admitted for pain control, bleeding from the lesion itself or mechanical renal obstruction.

With pain admissions, standing doses of opioids with as needed (PRN) doses for breakthrough pain are indicated. If admitted for vaginal bleeding, repeat complete blood count (CBC) tests with a listed transfusion threshold noted, usually at less than 7 g/dL.

If admitted for renal obstruction, monitor urine output and creatinine until nephrostomy tubes are placed. Long-acting opioids should not be used in the setting of renal obstruction or concern for impending renal obstruction from tumor burden because of decreased clearance of narcotics in the setting of renal failure.

B. Anticipated Length of Stay.

If admitted for any of the complications listed above (pain, bleeding or renal obstruction), then goals of care are pain management, a stable hemoglobin or relief of the obstruction.

C. When is the Patient Ready for Discharge.

If admitted for any of the complications related to cervical cancer (pain, bleeding, obstruction), the patient is ready for discharge once pain can be managed with an oral regimen, hemoglobin is stable indicating hemostasis, or creatinine has stabilized.

D. Arranging for Clinic Follow-up

The patient should be followed-up in the gynecology clinic as well as the oncology clinic once diagnosed with cancer. Pre-invasive lesions (ASC-US/HPV+, ASC-H, LSIL, HSIL) should be followed solely by gynecology.

1. When should clinic follow up be arranged and with whom.

Clinic follow-up should be scheduled within 4 weeks of discharge in the gynecology office.

2. What tests should be conducted prior to discharge to enable best clinic first visit.

A cell blood count (CBC) and creatinine should be checked pre-discharge in order to ensure that they are stable.

3. What tests should be ordered as an outpatient prior to, or on the day of, the clinic visit.

A CBC and creatinine should be checked on the day of the clinic visit in order to ensure they are stable.

E. Placement Considerations.

N/A

F. Prognosis and Patient Counseling.

Prognosis of cervical cancer depends on the stage of diagnosis. The 5-year relative survival rate for the earliest stage of ICC is 92%, and the overall 5-year survival rate is about 72% with treatment. With progression of the stage, prognosis worsens. Only 25-35% of women with stage III cancer and less than 15% of those with stage IV cancer are alive after five years.

VI. Patient Safety and Quality Measures

A. Core Indicator Standards and Documentation.

N/A

B. Appropriate Prophylaxis and Other Measures to Prevent Readmission.

Because of the hypercoagulable state associated with solid malignancies, all patients admitted with cervical cancer should receive deep vein thrombosis prophylaxis with subcutaneous heparin or Lovenox unless they are having significant vaginal bleeding from the tumor.

VII. What's the Evidence?

"2012 American Society for Colposcopy and Cervical Pathology Consensus Guidelines Conference. 2012 Updated Consensus Guidelines for the Management of Abnormal Cervical Cancer Screening Tests and Cancer Precursors". Journal of Lower Genital Tract Disease. vol. Volume 17. 2013. pp. S1-27.

"American Cancer Society, American Society for Colposcopy and Cervical Pathology, and American Society for Clinical Pathology Screening Guidelines for the Prevention and Early Detection of Cervical Cancer". Journal of Lower Genital Tract Disease. vol. Volume 16. 2012. pp. 175-204.

"Recent consensus guidelines published on screening and management guidelines for cervical cancer".

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