Endocervical squamous metaplastic cells present

Contents

No Endocervical Cells on Pap Test?

A Pap smear involves lightly scraping the surface of the cervix to collect cells. A pathologist then examines a Pap smear under a microscope, looking for two types of cervical cells: squamous cells, which are typically found in the outer surface of the cervix, and columnar endocervical cells, which come from the lining of the narrow opening in the cervix leading to the inside of the uterus (the endocervical canal).

Pathologists report on the appearance of both types of cells, and they report if no endocervical cells are seen, as in your case. Your ob-gyn is correct that this is not unusual in a woman who has gone through menopause. The reason is that after menopause, the cervix may be less pliable and the transformation zone (the section of the endocervical canal where squamous cells begin to change to columnar cells) moves higher up the cervical canal, making it more difficult to routinely obtain endocervical cells. However, in a premenopausal woman, the transformation zone is fairly close to the opening of the cervix, allowing the smear to capture both types of cells easily.

It will probably be reassuring to you to know that all the Pap smears that you have had did indeed look at the surface cells of the cervix, so the test has still been useful. Women whose Pap smears show no endocervical component but who have had otherwise normal results and are not seeing abnormal bleeding or other symptoms generally do not need another Pap smear performed until the next annual examination.

At your next yearly exam, you could discuss with your ob-gyn your concern about prior Pap smears lacking an endocervical component. He or she may be able to make a special effort to reach the endocervical canal with the Pap instrument. Sometimes, if it is difficult to reach the cervical canal, a small brush can be inserted into the canal to obtain the endocervical component.

Learn more in the Everyday Health Cancer Center.

Endocervical Cells In a Pap Smear: A Concept Changed

July 15, 2014

The National Cancer Institute-sponsored Bethesda Workshop of 2001 gathered national experts to devise recommendations for reporting of cervical cytology results. In the second edition of their published conclusions, the experts downplayed the significance of endocervical cells in the Pap smear, with their new recommendations no longer deeming Pap collections lacking endocervical cells as “unsatisfactory.”

Twenty years ago, the significance of an endocervical component was considered an indicator of specimen adequacy. Researchers of the era concluded that the presence of endocervical cells in a Pap smear was associated with a lower false-negative rate for cervical neoplasia, and that endocervical canal sampling should therefore be part of the routine Papanicolaou test. They also suggested that cytology reports on cyclic women should indicate the presence or absence of endocervical cells. A few subsequent studies have reported a relationship between the identification of an endocervical component and the rate of detection of squamous intraepithelial lesions.

Although some studies have reported that squamous intraepithelial lesion (SIL) cells are more prevalent in specimens in which endocervical /transformation zone (EC/TZ) cells are present, other studies have found no difference in SIL detection related to EC/TZ status or the studies found that there was no increase in SIL detection over time when devices promoting increased EC/TZ collection were used.

Several studies have shown that women with smears lacking EC/TZ cells are not more likely to have squamous lesions on follow up than are women with EC/TZ cells. Finally, retrospective case-control studies have failed to show an association between false-negative interpretations of Paps and lack of EC/TZ cells.

We do know that endocervical cells are less frequently identified in women who use oral contraceptives, are pregnant, or are postmenopausal. Clinician education, improved technique, modern sampling devices and experience tend to increase the collection of EC/TZ cells. However, despite good collection technique and use of appropriate endocervical sampling devices, some women still have repeated Pap tests that lack EC/TZ cells.

Evidence-based medicine relies on the medical literature. Previously, the belief was that no endocervical cells in a Pap smear was a reason for concern with patients often asked to return for retesting or other treatment recommended. Today, we know there are many reasons accounting for the lack of endocervical cells in a Pap specimen and because the literature conflicts on this subject, the Bethesda System has revised its guidelines on recommended follow up for this finding.

A repeat Pap test in 12 months is now the recommended management for women with a satisfactory Pap either (1) lacking EC/TZ component or (2) exhibiting partially obscuring factors: excess blood, etc. This approach is a reasonable compromise in light of the conflicting data regarding the significance of an EC/TZ component cited above and the paucity of data on other obscuring indicators. While longitudinal studies fail to show that women lacking such components are at increased risk for squamous lesions, cross-sectional studies show differing results.

Publications Findings
Tacken MA. Loss to follow-up of cervical smears without endocervical columnar cells is not disturbing. Eur J Gynaecol Oncol. 2006;27(1):42-6. The majority of women with Pap smears having no endocervical cells did not have any abnormalities in the subsequent Pap smear.
Izadi Mood N. Endocervical and metaplastic cells: comparison of endocervical and metaplastic cell number in Papanicolaou smears with and without squamous intraepithelial lesion. Acta Cytol. 2006 Mar-Apr; 50(2):178-80 There is no correlation between increased risk of squamous intraepithelial lesion (SIL) in women with smears lacking endocervical cells compared to smears that have endocervical cells. However, there is correlation between women having smears containing metaplastic cells, which are more likely to have SIL than smears without metaplastic cells.
Siebers AG. Prevalence of squamous abnormalities in women with a recent smear without endocervical cells is lower as compared to women with smears with endocervical cells.Cytopathology. 2003 Apr;14(2):58-65. The rate of squamous lesions in women having recent Pap smears which lack endocervical cells is significantly lower than in the women with smears having endocervical cells.
Y L Hock. Outcome of women with inadequate cervical smears followed up for five years. J Clin Pathol 2003;56:592–595 Women who lack endocervical cells in repeated Pap smears did not have a significant increased risk for high grade CIN over the five years of this study. However, increased risk was found in women whose Pap smears were “obscured by polymorphs.”
Kabbani W. Cell block findings from residual PreservCyt samples in unsatisfactory ThinPrep Paps: no additional benefit. Diagn Cytopathol. 2002 Oct;27(4):238-43. No clinically significant pathologic findings were found on cell blocks (concentrations of liquid-based Paps) performed on previously unsatisfactory Paps. A repeat Pap smear at the next routine visit was felt to be the most cost-effective follow-up protocol since a large majority of lesions identified in the study were low-grade squamous intraepithelial type.
Selvaggi SM. Endocervical component: is it a determinant of specimen adequacy? Diagn Cytopathol. 2002 Jan;26(1):53-5. There was no significant difference in the detection of high-grade squamous intraepithelial lesion (HSIL) in Pap smears that contained endocervical cells when compared to Pap smears than did not.
Mitchell HS. Longitudinal analysis of histologic high-grade disease after negative cervical cytology according to endocervical status. Cancer. 2001 Aug 25;93(4):237-40. Lack of endocervical cells in Pap smears does not justify short-interval repeat testing because there was not a higher rate of histologic high-grade abnormalities on longitudinal follow up.
Bos AB. Endocervical status is not predictive of the incidence of cervical cancer in the years after negative smears. Am J Clin Pathol. 2001 Jun;115(6):851-5. No significant differences were seen in proportions of pre-invasive lesions found in women after having negative Pap smears without endocervical cells when compared to negative Pap smears which did have endocervical cells.

The Bethesda System For Reporting Cervical Cytology – Definitions, Criteria and Explanatory Notes, 2nd Edition states:

“Specimens that lack EC/TZ elements are not more likely to have a squamous lesion on follow up.”

“Since data is unclear regarding the significance of EC/TZ elements, a repeat Pap smear in 12 months is generally suggested.”

Cervical / Vaginal Specimens

The National Cancer Institute has published the third edition of “The Bethesda System for Reporting Cervical Cytology,” which refines the reporting system developed in the 2014 Bethesda System Update. The 2014 Bethesda System has been expanded and revised to take into account the advances and experiences in the past decade, while clarifying various technologies and morphologic questions. LabCorp believes that the Bethesda System promotes consistent communication and clarity in reporting cervical cytopathology results. The terminology is detailed below.

The 2014 Bethesda System for Reporting Cervical / Vaginal Cytology

Specimen Type

  • Indicate conventional smear (Pap smear) vs. liquid-based preparation vs. other

Specimen Adequacy

  • Satisfactory for evaluation (describe presence or absence of endocervical/transformation zone component and any other quality indicators, e.g., partially obscuring blood, inflammation, etc.)
  • Unsatisfactory for evaluation … (specify reason)
    • Specimen rejected/not processed (specify reason)
    • Specimen processed and examined but unsatisfactory for evaluation of epithelial abnormality because of (specify reason)

General Categorization (Optional)

  • Negative for intraepithelial lesion or malignancy
  • Other: See Interpretation/Result (e.g., endometrial cells in a woman ≥45 years of age)
  • Epithelial cell abnormality: See Interpretation/Result (specify “squamous” or “glandular” as appropriate)

Interpretation/Result

  • Negative for intraepithelial lesion or malignancy (When there is no cellular evidence of neoplasia, state this in the General Categorization above and/or in the Interpretation/Result section of the report, whether or not there are organisms or other non- neoplastic findings)

Non-neoplastic Findings (optional to report; list not inclusive)

  • Non-neoplastic cellular variations
    • Squamous metaplasia
    • Keratotic changes
    • Tubal metaplasia
    • Atrophy
    • Pregnancy-associated changes
  • Reactive cellular changes associated with:
    • Inflammation (includes typical repair)
    • Lymphocytic (follicular) cervicitis
    • Radiation
    • Intrauterine contraceptive device (IUD)
  • Glandular cells status post hysterectomy

Organisms

  • Trichomonas vaginalis
  • Fungal organisms morphologically consistent with Candida spp.
  • Shift in flora suggestive of bacterial vaginosis
  • Bacteria morphologically consistent with Actinomyces spp.
  • Cellular changes consistent with herpes simplex virus (HSV)
  • Cellular changes consistent with cytomegalovirus

Other

  • Endometrial cells (in a woman ≥45 years of age) (Specify if “negative for squamous intraepithelial lesion”)

Epithelial Cell Abnormalities

  • Atypical squamous cells
    • of undetermined significance (ASC-US)
    • cannot exclude HSIL (ASC-H)
  • Low-grade squamous intraepithelial lesion (LSIL) (encompassing: HPV/mild dysplasia/CIN 1)
  • High-grade squamous intraepithelial lesion (HSIL) (encompassing: moderate and severe dysplasia, CIS; CIN 2 and CIN 3)
    • with features suspicious for invasion (if invasion is suspected)
  • Squamous cell carcinoma

Glandular Cell

  • Atypical
    • endocervical cells (NOS or specify in comments)
    • endometrial cells (NOS or specify in comments)
    • glandular cells (NOS or specify in comments)
  • Atypical
    • endocervical cells, favor neoplastic
    • glandular cells, favor neoplastic
  • Endocervical adenocarcinoma in situ
  • Adenocarcinoma
    • endocervical
    • endometrial
    • extrauterine
    • not otherwise specified (NOS)

Other Malignant Neoplasms (specify)

  • Provide a brief description of the test methods and report the result so that it is easily understood by the clinician.

Computer-assisted Interpretation of Cervical Cytology

  • If case is examined by automated device, specify device and result.

Educational Notes and Comments (Optional)

  • Suggestions should be concise and consistent with clinical follow- up guidelines published by professional organizations (references to relevant publications may be included).

Reference

1. Nayar, Ritu and Wilbur, David C, eds. The Bethesda System for Reporting Cervical Cytology. Definitions, Criteria and Explanatory Notes. Third Edition. Springer International Publishing Switzerland; 2015.

The Pap Test: Cervical Changes and Further Testing

Did you have a recent Pap smear that showed abnormal changes in the cells of your cervix or a positive HPV test and you need further testing? This article will help you understand the Pap and HPV test results and the most likely plan for follow up.

What is a Pap Test?

The Pap test, also called a “Pap smear” was introduced as a screening test for cervical cancer in 1943 by Dr. George Papanicolaou, for whom the test is named. The Pap test involves taking cells from the cervix, which is located at the top of the vagina, using a small brush or other tool. The sample is sent to a laboratory where it is examined for abnormal appearing cervical cells. A small percentage of abnormal cells can become cancer.

In many women, providers also use a test to detect Human Papilloma Virus (HPV) in conjunction with the pap test for cervical cancer screening. The large majority of cervical cancers are caused by certain “high-risk” strains of HPV. This test looks for these high-risk types of HPV in the cervical cells. This gives your provider more information about a possible cause of an abnormal pap result and helps to determine the next steps.

When should cervical cancer screening be done?

All women should begin cervical cancer screening at age 21.

Screening guidelines:

  • Age 21-29: Pap testing done every 3 years. HPV testing is only used if the Pap test is abnormal.
  • Age 30-65: Pap testing and HPV test done every 5 years. Alternatively, a woman could have a Pap test alone every 3 years.
  • Over age 65: women who have had normal Pap results can stop testing all together.
  • Women over age 65 who have a history of a serious cervical pre-cancer should continue to be tested for 20 years after that diagnosis, even if this means screening will continue past age 65.
  • Even if you have had the HPV vaccine, you should still continue to have Pap testing based on your age in the above guidelines.

Some women with certain risk factors may need more frequent screening. These risk factors include being infected with human immunodeficiency virus (HIV), being immunosuppressed, having been exposed to diethylstilbestrol (DES) before birth, and having been previously treated for certain cervical abnormalities or cancer.

Please see the ACS document, Cervical Cancer Prevention and Early Detection for more information.

How is the screening done?

During the gynecologic examination, a speculum is inserted into the vagina so that the cervix and vagina can be seen. The doctor or nurse inserts a cotton-tipped swab or small brush into the cervical opening (cervical os) to sample endocervical cells (which come from the area most at risk for cervical cancer).

Normal vaginal discharge contains cells that are shed from the cervix and uterus. Samples of these cells are taken for the Pap test. For this reason, you should not douche, have vaginal intercourse, use tampons or vaginal medication for 48 hours before the Pap test is done.

The samples are sent to a pathologist for detailed examination under a microscope. A report is sent to your doctor with a classification of the test results and a description of the cell changes. It can take up to three weeks to receive your results. An HPV test, looking for certain strains of the HPV virus associated with cervical cancer, can also be sent using the same sample.

Process of Cervical Changes

The cervix is the part of the uterus that extends into the vagina. There are two types of cells that line the cervix, one lines the outer cervix (portio) and another lines the inner cervix (endocervix). There is a distinct junction between the two cell types called the transformation zone. The Pap test is taken from this area because this where dysplasia (pre-cancer) and cancer most often arise.

Two common changes in cells are metaplasia and dysplasia.

Metaplasia – Metaplasia is generally described as a process of cell growth or cell repair that is benign (not cancerous). This process normally occurs in unborn babies, during adolescence, and with the first pregnancy. Studies have shown that metaplasia is present in more than one-half of all women at some point in their development. This is a normal finding and does not indicate cancer.

Dysplasia – In dysplasia, there is an increase in the number of cells formed, which do not mature as expected. This changes the inside of the cell. The higher the grade of dysplasia found on the cervix, the more likely that it will progress to invasive cancer. For this reason, dysplasia is thought of as a “pre-cancerous” condition. Dysplasias are almost always curable if managed appropriately. Although some mild dysplasias (LSIL) will regress without treatment, it is not possible to distinguish between dysplastic areas of the cervix that will return to normal and dysplastic areas which will progress and ultimately become cancer. In turn, these results require further testing.

Causes of Cervical Cell Changes

Inflammation often results in a mildly abnormal Pap test, resulting in the diagnosis of ASCUS in the Bethesda System or changes consistent with Human Papilloma Virus (HPV) infection. An inflamed cervix may appear red, irritated, or eroded. Some of the common causes of cervical inflammation are:

  • Bacteria (from an infection).
  • Viruses, especially herpes infections and condyloma cuminata (warts).
  • Yeast or monilia infections.
  • Trichomonas infections.
  • Pregnancy, miscarriage, or abortion.
  • Chemicals (for example, medications).
  • Hormonal changes.

When the inflammation is treated, repair of the tissues through metaplasia usually will follow. In several months, a repeat Pap test will often then be normal.

Classification of Squamous Cells on the Pap Test

Several different classification schemes have evolved over the years for characterizing Pap test results. Unfortunately, this is a continuing source of confusion. The most commonly used classification scheme is the Bethesda System.

  • ASC – atypical squamous cells. This is the most common abnormal finding in Pap tests. The Bethesda System divides this category into two groups:
    • ASC-US – atypical squamous cells of undetermined significance. The squamous cells do not appear completely normal, but doctors are uncertain about what the cell changes mean. Sometimes the changes are related to HPV infection, but they can also be caused by other factors such as pregnancy. For women who have ASC-US, her cells may then be tested for the presence of high-risk HPV. If HPV is present, colposcopy (see below) will usually be done. Alternatively, the pap test may be repeated in 6 months, and if normal, she may resume the usual schedule of screening. If a woman has ASC-US on her pap with a negative test for high-risk subtypes of HPV, a pap and HPV test may just be repeated in one year without further testing.
    • ASC-H – atypical squamous cells, cannot exclude a high-grade squamous intraepithelial lesion. Intraepithelial refers to cells on the surface of the cervix. ASC-H cells do not appear normal, but doctors are uncertain about what the cell changes mean. However, there is a possibility that a pre-cancerous lesion is developing, so a colposcopy is recommended.
  • LSIL – low-grade squamous intraepithelial lesion; this is the earliest pre-cancerous lesion. LSILs may be referred to as mild dysplasia or as cervical intraepithelial neoplasia type 1 (CIN-1). Although many LSIL lesions will resolve on their own, there is no way to predict which ones will resolve, so doctors will typically perform a colposcopy.
  • HSIL – high-grade squamous intraepithelial lesion. HSILs are more abnormal-looking than LSILs and have a higher likelihood of progressing to cancer. HSILs include lesions that in other classification systems may be referred to as moderate or severe dysplasia, carcinoma in situ, and/or CIN-2 and CIN-3. A finding of HSIL necessitates a colposcopy.
  • Squamous cell carcinoma is the most advanced category. This means that abnormal cervical squamous cells have invaded into the cervix. A finding of squamous cell carcinoma requires further testing and treatment. Keep in mind, when women undergo appropriate screening, most of the time, abnormalities in the cervix are detected and treated before they have had the chance to progress to cervical cancer.

Classification of Glandular Cells on the Pap Test

Glandular cells, which produce mucus, are found in the opening of the cervix and in the uterus. Abnormalities in these cells are more difficult to classify. Glandular cells that are seen on the Pap test most commonly come from the endocervix (area closest to the uterus). However, other glandular epithelial surfaces in the female reproductive tract may shed cells that are visible on the Pap test. Endometrial cells may also appear on Pap tests and reveal underlying abnormalities. Because the female reproductive tract is open to the abdominal cavity via the fallopian tubes, occasionally, cells from the ovary, fallopian tubes, peritoneum or other abdominal organs may be seen on the Pap smear. Glandular cells on the Pap test are classified as follows:

  • Endometrial cells, cytologically benign, in a postmenopausal woman.
  • Atypical glandular cells (AGC, formerly AGUS) that should be qualified further, if possible, as to whether a reactive or neoplastic process is favored. A finding of AGC will typically be followed by a colposcopy and possibly also endometrial sampling.
  • Endocervical Adenocarcinoma.
  • Endometrial Adenocarcinoma.
  • Extrauterine Adenocarcinoma (e.g. ovarian, Fallopian tube, pancreas, etc.).
  • Adenocarcinoma, not otherwise specified (i.e. unknown primary site).

HPV DNA TEST

The HPV test can be used for screening or as a next step after an abnormal pap test result. There are over 150 types of HPV, but only 14 types are thought to be “high-risk” for causing various types of cancer. Two of these types (16 & 18) are known to cause over 70% of cervical cancers. The HPV test looks for the highest risk types of HPV in the same sample used for the pap test. The results of the HPV test along with the pap test and your age and health will determine what the next steps will be.

Colposcopy: The next diagnostic step

An abnormal Pap smear result often requires further evaluation. If the abnormality is minor (i.e. inflammation, or HPV changes) your healthcare provider may choose to repeat the Pap test in a few months, as your own immune system may “clear” the HPV infection and a follow up Pap be normal. If the abnormalities have persisted or worsened, colposcopy is indicated. Colposcopy will enable your provider to make a more accurate diagnosis.

Colposcopy – A colposcope is a lighted microscope that is used to magnify the cervical tissue during a pelvic examination. The colposcope is used to visualize abnormal areas of the cervix and vagina that are too small to see with the naked eye. The entire transformation zone must be seen. The colposcopic examination is an office procedure and may be a bit more uncomfortable than a routine pelvic examination because of the pressure from the speculum lasting longer than a typical Pap test. The test takes 5 to 10 minutes to perform. During the examination, the examiner may take small samples of cervical tissue (biopsies), which are later examined by a pathologist. These diagnostic biopsies will guide further management.

From the examiner’s perspective

From the patient’s perspective

Treatment Options for Cervical Dysplasia

Cone Biopsy – A cone biopsy (also called cold knife cone biopsy) is a minor operation, which is usually performed in an outpatient surgical facility. In the operating room, the physician removes a small cone-shaped tissue sample from your inner cervix. This tissue is sent to a pathologist for detailed examination under a microscope. This procedure does not remove any of your reproductive organs and should have little impact on your future ability to become pregnant. If only dysplasia is found in the cone specimen, then often no additional treatment will be required. However, if invasive cancer is discovered, additional treatment (i.e. surgery or radiation therapy) is indicated. Therefore, a cone biopsy may be considered as therapeutic (if all of the dysplasia is removed) or diagnostic (if it discovers a worse problem that requires additional treatment).

Loop Electrosurgical Excision Procedure (LEEP) – The LEEP procedure is similar to a cone biopsy in that it removes a tissue sample from your cervix, which is then examined, under a microscope, by a pathologist. It may also be called an LLETZ (large loop excision of the transformational zone). The LEEP procedure uses a low voltage, electric wire to cut away the abnormal area and has the advantage of being easily performed in the office with local anesthesia. However, the LEEP procedure and cone biopsy are not equivalent and your physician will recommend which is the best option, depending on your case.

Cryosurgery – Cryosurgery is another treatment option that can be performed in the doctor’s office. During the procedure, the doctor freezes and thereby destroys the dysplasia on your cervix. You may notice a brief unpleasant cold sensation during the freezing procedure. A disadvantage of cryosurgery is that no specimen is obtained for the pathologist to examine in order to exclude the possibility of invasive cancer.

If you have questions about your Pap test or the results of your test it is best to speak to your provider.

The Pap (Papanicolaou) Test

The health care professional first places a speculum inside the vagina. The speculum is a metal or plastic instrument that keeps the vagina open so that the cervix can be seen clearly. Next, using a small spatula or brush, a sample of cells and mucus is lightly scraped from the exocervix (see illustration in What is Cervical Cancer? ). A small brush or a cotton-tipped swab is then inserted into the opening of the cervix to take a sample from the endocervix . If your cervix has been removed (because you had a trachelectomy or hysterectomy) as a part of the treatment for a cervical cancer or pre-cancer, the cells from the upper part of the vagina (known as the vaginal cuff) will be sampled. The samples are then looked at in the lab.

Although the Pap test has been more successful than any other screening test in preventing a cancer, it’s not perfect. One of the limitations of the Pap test is that the results need to be examined by the human eye, so an accurate analysis of the hundreds of thousands of cells in each sample is not always possible. Engineers, scientists, and doctors are working together to improve this test. Because some abnormalities may be missed (even when samples are looked at in the best labs), it’s best to have this test regularly as recommended by the American Cancer Society guidelines .

Making your Pap tests more accurate

You can do several things to make your Pap test as accurate as possible:

  • Try not to schedule an appointment for a time during your menstrual period. The best time is at least 5 days after your period stops.
  • Don’t use tampons, birth-control foams or jellies, other vaginal creams, moisturizers, or lubricants, or vaginal medicines for 2 to 3 days before the Pap test.
  • Don’t douche for 2 to 3 days before the Pap test.
  • Don’t have vaginal sex for 2 days before the Pap test.

A pelvic exam is not the same as a Pap test

Many people confuse pelvic exams with Pap tests. The pelvic exam is part of a woman’s routine health care. During a pelvic exam, the doctor looks at and feels the reproductive organs, including the uterus and the ovaries and may do tests for sexually transmitted disease. Pelvic exams may help find other types of cancers and reproductive problems. A Pap test can be done during a pelvic exam , but sometimes a pelvic exam is done without a Pap test. A Pap test is needed to find early cervical cancer or pre-cancers so ask your doctor if you had a Pap test with your pelvic exam.

How Pap test results are reported

The most widely used system for describing Pap test results is the Bethesda System (TBS). There are 3 main categories, some of which have sub-categories:

  • Negative for intraepithelial lesion or malignancy
  • Epithelial cell abnormalities
  • Other malignant neoplasms.

You may need further testing if your Pap test showed any of the abnormalities below. See Work-up of Abnormal Pap Test Results.

Negative for intraepithelial lesion or malignancy

This category means that no signs of cancer, pre-cancer, or other significant abnormalities were found. There may be findings that are unrelated to cervical cancer, such as signs of infection with yeast, herpes, or Trichomonas vaginalis (a type of sexually transmitted disease), for example. Specimens from some women may also show “reactive cellular changes”, which is the way cervical cells appear when infection or other inflammation is around.

Epithelial cell abnormalities

This means that the cells lining the cervix or vagina show changes that might be cancer or a pre-cancer. This category is divided into several groups for squamous cells and glandular cells.

Squamous cell abnormalities

Atypical squamous cells (ASCs) This category includes two types of abnormalities:

  • Atypical squamous cells of uncertain significance (ASC-US) is used to describe when there are cells that look abnormal, but it is not possible to tell if this is caused by infection, irritation, or a pre-cancer. Most of the time, cells labeled ASC-US are not pre-cancer, but more testing, like an HPV test, is needed to be sure.
  • Atypical squamous cells where high-grade squamous intraepithelial lesion (HSIL) can’t be excluded (ASC-H) is used to describe when the cells look abnormal but are more concerning for a possible pre-cancer that needs more testing and may need treatment.

Squamous intraepithelial lesions (SILs) These abnormalities are divided into two categories:

  • In low-grade SIL (LSIL) the cells look mildly abnormal. This might also be called mild dysplasia or cervical intraepithelial neoplasia grade 1 (CIN1).
  • In high-grade SIL (HSIL) the cells look severely abnormal and are less likely than the cells in LSIL to go away without treatment. They are also more likely to eventually develop into cancer if they are not treated.This might also be called moderate to severe dysplasia or cervical intraepithelial neoplasia grade 2 or 3 (CIN2 and/or CIN3).

Further tests are needed if SIL is seen on a Pap test. If treatment is needed, it can cure most SILs and prevent invasive cancer from forming.

Squamous cell carcinoma: This result means that the woman is likely to have an invasive cancer. Further testing will be done to be sure of the diagnosis before treatment can be planned.

Historically, the presence of an endocervical/transformation (EC/TZ) component was considered a measurement of quality of the Pap test, implying that the transformation zone was adequately sampled, which indirectly represents the competence of the individual performing the Pap test, or the individual (cytotechnologist or pathologist) interpreting the Pap. The phrase ‘no endocervical component present’ carries negative connotations for both the clinician, the patient and is occasionally met with questions and concern. However, there are several reasons why an EC/TZ component may not be present. These are absolutely independent of clinician skill or collection method. In our experience, bacterial vaginosis and fungal infections may cause an increased likelihood of EC/TZ absence. Also, increased age results in the transformation zone migrating higher in the endocervical canal,making sampling more difficult. A combination of cytobrush and spatula usually yields an adequate EC/TZ component. Additionally, multiple recent studies have shown that the absence of endocervical cells is NOT associated with a higher risk of cervical disease. Longitudinal studies have demon-strated that women whose Pap tests did not contain endocervical cells were not at higher risk than those who did show endo-cervical cells in their Pap test. The current ASCCP guidelines have changed to reflect this new evidence1 Negative Pap tests with absent EC/TZ components have been shown to have the same risk for CIN 3+ over time, as women with EC/TZ present on Pap2-4 Additionally, high risk HPV testing is apparently independent of TZ sampling-5which offers an additional margin of safety for women when co-testing is performed, which is one of the many reasons why we advocate co-testing.

Article Highlights:

  • Patient Age, Bacterial Vaginosis or Candida infections may cause a lack of an EC/TZ component.
  • The lack of EC/TZ component is not related to clinician skill.
  • Recent evidence shows no increased risk for patients without EC/TZ on Pap test and earlier, repeat testing is not necessary.

The MatrixBrush, exclusive to PathAdvantage, offers a more comfortable method of endometrial sampling, that retains diagnostic accuracy and sensitivity.

BIBLIOGRAPHY 1 https://www.asccp.org/Guidelines 2 Mitchell HS. Longitudinal analysis of histologic high grade disease after negative cervical cytology according to endocervical status. Cancer 2001;93:237Y40 3 Elumir-Tanner L, Doraty M. Management of Papanicolaou test results that lack endocervical cells. CMAJ 2011; 183:563Y8. 4 Huang A, Quinn M, Tan J. Outcome in women with no endocervical component on cervical cytology after treatment for high-grade cervical dysplasia. Aust NZ J Obstet Gynaecol 2009;49:426Y8. 5 Zhao C, Austin RM. Human papillomavirus DNA detection in ThinPrep Pap test vials is independent of cytologic sampling of the transformation zone. Gynecol Oncol 2007; 107:231Y5. Article written by PathAdvantage pathologists Richard Hopley, MD and Collin O’Hara, MD.

Normal Cytology

Negative for Intraepithelial Lesions or Malignancy (NILM)

The category of Negative for Intraepithelial Lesion Malignancy (NILM) indicates that the specimen was adequate for evaluation and that the cells present showed no evidence of abnormality. There are several types of cells examined for abnormalities. They are:

  • Superficial Squamous Cells
  • Intermediate Squamous Cells
  • Squamous Metaplastic Cells
  • Mature Squamous Metaplasia
  • Immature Squamous Metaplasia
  • Parabasal Cells
  • Endocervical Cells

Other normal cells that are occasionally found on a Pap smear:

  • Ciliated Endocervical Cells
  • Endometrial Cells
Superficial Squamous Cells

The superficial squamous cell comprises the outermost layer of the non-keratinizing epithelium. The 1,604 µm eosinophillic polygonal shaped cell houses a 25 µm centrally placed pyknotic nucleus. No nuclear detail can be seen due to nuclear degeneration. Superficial squamous cells are seen in abundance during the late proliferative and ovulatory phases of the menstrual cycle. At these points, estrogen is at its peak.

Intermediate Squamous Cells

The polygonal-shaped intermediate squamous cell size ranges 1,256-1,618 µm. The cell is found in the stratum spongiosum (midzone) layer of the squamous epithelium. The intermediate cell’s cytoplasm is thin, transparent, and typically stains basophilic. The centrally placed nucleus is 35 µm. The nucleus is vesicular with fine evenly dispersed granular chromatin. Intermediate squames are seen in abundance when progesterone is at high levels. This occurs during the luteal and early follicular phases of the menstrual cycle, and the second and third trimester of pregnancy.

Squamous Metaplastic Cells

Squamous metaplastic cells are round to polygonal in shape with dense biphasic staining cytoplasm and round centrally located nuclei. They arise from the basal layer of glandular epithelium as a protective response to stimuli, creating the transformation zone. These metabolically active cells are often the site where abnormalities occur. Throughout a woman’s lifetime, the transformation zone regresses from the ectocervix and up into the endocervical canal.

Parabasal Squamous Cells

Parabasal squamous cells are found in the basal layer of the squamous epithelium. The round- to oval-shaped cell is 318-706 µm in size. The dense homogenous basophilic cytoplasm encloses a 50 µm nucleus. The nuclear detail reveals a finely granular chromatin. Parabasals are an uncommon finding on Pap smears of women with estrogen production or replacement hormone. These cells are often seen in patients who lack estrogen, including those who are premenstrual, post partum, taking estrogen-restricting hormones, or postmenopausal.

Endocervical Glandular Cells

The tall, columnar-shaped endocervical cell is 188 µm in size. The mucinous cytoplasm of endocervical cells are visualized as being granular or vacuolated. The 50 µm round basally placed nucleus reveals a fine granular chromatin with an occasional nucleoli. Endocervical cells can be seen on Pap tests in three arrangements: single cells, as strips, or as a sheet.

Endometrial Glandular Cells

Endometrial cells are small and cuboidal, averaging 10-20 µm. The nuclei are hyperchromatic and may be round- to oval- to bean-shaped. In cycling women, endometrial cells are expected to be seen on Pap tests from the first day bleeding starts through the twelfth day. After day twelve, the presence of endometrial cells may be considered a significant finding. However, the patient’s age and any exogenous hormones being taken play a role in these “out-of-phase” endometrial cells.

Interpretation of Endocervical Cells With Gastric-Type Mucin on Pap Smears: A Proposal for a Cytologic Category “Atypical Endocervical Cells With Gastric-Type Mucin”

Abstract

Objectives

Early detection of endocervical adenocarcinoma is especially important for cancers that are human papillomavirus (HPV) negative. We investigated the clinicopathologic significance of yellow gastric-type mucin observed on Papanicolaou smears.

Methods

We described “atypical endocervical cells with gastric-type mucin” (AEC-GAM) when yellow mucin was observed in endocervical cells. We retrieved AEC-GAM samples from 58,752 cervical smears performed at Yamanashi University Hospital during our study period and reviewed clinical, cytologic, and pathologic features.

Results Conclusions

Yellow mucin is a diagnostic clue for endocervical glandular lesions with gastric differentiation. We recommend describing AEC-GAM on cytologic reports to improve cytologic screening for HPV-negative cervical cancers.

The incidence of adenocarcinoma of the uterine cervix has increased in recent years, and it currently comprises approximately 10% to 25% of all cervical cancers.1-3 The detection of early endocervical adenocarcinoma is a critical issue for the management of patients. However, the subtle cytologic and colposcopic features of early endocervical adenocarcinoma and the lack of clearly defined precursor lesions make early detection challenging.4,5

High-risk human papillomavirus (HPV) DNA testing combined with Papanicolaou (Pap) smear testing (cotesting) is useful for cervical screening.6 However, HPV DNA is negative in a minor subset of cervical adenocarcinoma.7 A Japanese study found that gastric-type mucinous carcinoma (GMC), including minimal deviation adenocarcinoma (MDA), appears in approximately 25% of cervical adenocarcinoma; GMC is a high-risk HPV-negative cancer.3,8,9 Lobular endocervical glandular hyperplasia (LEGH) is a benign hyperplastic lesion of the endocervical glands.10 Recent studies suggest that LEGH is a high-risk HPV-negative lesion that may be a precursor of some types of adenocarcinoma, including GMC and MDA.9,11-16 The presence of these HPV-negative adenocarcinomas and their precursors can confuse the results of cervical screen cotesting.

LEGH and GMC produce pyloric gland mucin that shows gastric differentiation in these cells. Furthermore, HIK1083 and MUC6, antibodies against pyloric gland mucin, are immunopositive in these lesions.12,14,17,18 We previously reported that detection of gastric-type mucin in vaginal discharge using the HIK1083-labeled latex agglutination test (HIK1083 latex test) is useful for detecting LEGH and GMC.15

On a conventional Pap smear, gastric-type mucin shows up as cytoplasmic yellow mucin, while normal endocervical, glandular, cytoplasmic mucin has a pinkish color.18,19 Thus, screening for endocervical cells possessing yellow mucin on a Pap smear provides a diagnostic clue for the presence of LEGH and thus the presence of adenocarcinoma associated with LEGH and GMC. In this study, we prospectively evaluated the clinical importance of yellow mucin on conventional Pap smears.

Materials and Methods

We enrolled patients who received cytologic smears at the Department of Obstetrics and Gynecology, Yamanashi University Hospital, Yamanashi, Japan, between January 2000 and December 2016. All Pap smears were prepared by conventional methods. We used the Cytobrush Plus (CooperSurgical, Trumbull, CT) for cervical smears, and the Endocyte endometrial sampler (Laboratoire, Paris, France) or the Softcyte (Soft Medical, Tokyo, Japan) for endometrial smears. All patients provided their informed consent.

When yellow mucin was observed in endocervical cells on a Pap smear, we described it as “atypical endocervical cells with gastric-type mucin” (AEC-GAM) in addition to the original cytologic diagnoses. We also identified the finding as AEC-GAM when endocervical cells with yellow mucin were observed on endometrial smears.

To confirm gastric-type mucin, we used the finding of a “two-color pattern” in the same cytologic smear Image 1. All cytotechnologists and pathologists that assessed samples received special training for identifying gastric-type mucin. Two cytotechnologists independently performed cytologic screening on each smear. If their results were discordant, a third cytotechnologist, blinded to the previous assessments, was consulted. We recorded the concurrent judgment of two of these cytotechnologists, and cytopathologists finally confirmed the cytologic assessment of each case.

Image 1

Two-color pattern on Papanicolaou smear. Yellow color corresponds to gastric-type mucin (arrows), and pink color is normal endocervical mucin (arrowheads) (Papanicolaou stain, ×20).

Image 1

Two-color pattern on Papanicolaou smear. Yellow color corresponds to gastric-type mucin (arrows), and pink color is normal endocervical mucin (arrowheads) (Papanicolaou stain, ×20).

We performed HIK1083 latex tests on cervical mucus using the HIK1083 Latex Kit (Kanto Chemical, Tokyo, Japan) in all patients whose Pap smear samples contained endocervical cells with yellow mucin. We obtained patients’ cervical mucus by cotton swab within 1 month of the Pap smear tests. The latex agglutination test is positive if gastric-type mucin present in a cervical sample is greater than 1 U/mL (mucinous quantity having the antigen activity of 1 mg of p-nitrophenyl-N-acetyl-α-d-glucosaminide).15,20

Patients with watery vaginal discharge, multiple cervical cysts on vaginal sonography, endocervical cells with yellow mucin on Pap smear, and positive HIK1083 latex tests received a magnetic resonance imaging (MRI) examination to detect LEGH or malignancy. If patients did not have atypical cytologic findings, they were followed by cytology and vaginal sonography every 3 to 6 months. When cervical cancer was suspected by cytologic and/or imaging examination, we performed histologic examination, including cervical biopsy, endocervical curettage, and cone biopsy. For statistical analyses, we used the Mann-Whitney U test, with P values of less than .05 considered statistically significant.

Results

In this prospective study, 58,752 cervical smear samples and 30,346 endometrial smear samples were collected. There was AEC-GAM in 172 (0.29%) of the 58,752 cervical samples and 78 (0.26%) of the 30,346 endometrial samples, giving a total of 250/89,098 samples (0.28%). In paired samples of cervical and endometrial smears, 112 pairs showed AEC-GAM in the cervical and/or endometrial smear in the following combinations: only in the cervical smear, 36 pairs (32%); only endometrial smear, 28 pairs (25%); and both smears, 48 pairs (43%). In total, 250 cytologic samples with AEC-GAM were obtained from 74 patients. The rates at which we found AEC-GAM in either or both sample types increased gradually over our study period Figure 1.

Figure 1

The rate of detection of atypical endocervical cells with gastric-type mucin (AEC-GAM) in cytologic specimens.

Figure 1

The rate of detection of atypical endocervical cells with gastric-type mucin (AEC-GAM) in cytologic specimens.

Of the 74 patients from whom samples with AEC-GAM were obtained, nine sought a second opinion and 65 received additional workup and regular follow-up. Forty-one patients underwent hysterectomy due to the following preoperative diagnoses: cervical adenocarcinoma (six cases), adenocarcinoma in situ (AIS) (six cases), cervical squamous cell carcinoma (SCC) (one case), high-grade squamous intraepithelial lesion (one case), LEGH (22 cases), leiomyoma (three cases), adenomyosis (one case), and prolapses uteri (one case).

Postoperative histologic examination revealed 28 cases of LEGH and 13 cases of pyloric gland metaplasia (PGM) Table 1. Among 28 cases of LEGH, endocervical adenocarcinoma was found in eight cases: LEGH and AIS (five cases), LEGH and MDA (one case), LEGH and GMC (one case), and LEGH and usual-type endocervical adenocarcinoma (UEA) (one case) Image 2. Five cases of cervical carcinoma were found in the cases of PGM: PGM and AIS (one case), PGM and UEA (three cases), and PGM and SCC (one case).

Table 1

Histologic Diagnoses of Endocervical Cells With Yellow Mucin on Pap Smears

Histologic Diagnoses n
LEGH and AIS 5
LEGH and MDA 1
LEGH and GMC 1
LEGH and UEAa 1
LEGH only 20
PGM and AISa 1
PGM and UEAa 3
PGM and SCCa 1
PGM only 8
Total 41
Histologic Diagnoses n
LEGH and AIS 5
LEGH and MDA 1
LEGH and GMC 1
LEGH and UEAa 1
LEGH only 20
PGM and AISa 1
PGM and UEAa 3
PGM and SCCa 1
PGM only 8
Total 41

AIS, adenocarcinoma in situ; GMC, gastric-type mucinous carcinoma; LEGH, lobular endocervical glandular hyperplasia; MDA, minimal deviation adenocarcinoma; PGM, pyloric gland metaplasia; SCC, squamous cell carcinoma; UEA, usual-type endocervical adenocarcinoma.

aNo histologic relationship between LEGH/PGM and carcinoma.

Table 1

Histologic Diagnoses of Endocervical Cells With Yellow Mucin on Pap Smears

Histologic Diagnoses n
LEGH and AIS 5
LEGH and MDA 1
LEGH and GMC 1
LEGH and UEAa 1
LEGH only 20
PGM and AISa 1
PGM and UEAa 3
PGM and SCCa 1
PGM only 8
Total 41
Histologic Diagnoses n
LEGH and AIS 5
LEGH and MDA 1
LEGH and GMC 1
LEGH and UEAa 1
LEGH only 20
PGM and AISa 1
PGM and UEAa 3
PGM and SCCa 1
PGM only 8
Total 41

AIS, adenocarcinoma in situ; GMC, gastric-type mucinous carcinoma; LEGH, lobular endocervical glandular hyperplasia; MDA, minimal deviation adenocarcinoma; PGM, pyloric gland metaplasia; SCC, squamous cell carcinoma; UEA, usual-type endocervical adenocarcinoma.

aNo histologic relationship between LEGH/PGM and carcinoma.

Image 2 Image 2

Histology in five cases of AIS, one case of MDA, and one case of GMC suggested there was transformation from LEGH to AIS/adenocarcinoma. However, in one case of UEA coexisting with LEGH, a relationship between the two lesions was not observed on histology. Some minute lesions of PGM were found in one case of AIS, three cases of UEA, and one case of SCC.

We clinically diagnosed eight patients with LEGH due to watery vaginal discharge, yellow mucin on Pap smear, positive HIK1083 latex tests, and multiple cervical cysts seen on vaginal sonography and MRI. An additional 16 cases were clinically considered to be PGM because they did not show obvious cervical cystic lesions. In these 24 patients, follow-up continues, and endocervical cells with yellow mucin have been continuously observed.

Consequently, of 65 patients with AEC-GAM, 28 patients (43%) and 13 patients (20%) were histologically diagnosed with LEGH and PGM, respectively. We diagnosed a total of 36 patients (55%) with LEGH, including clinically diagnosed LEGH. The rate at which we found AIS/adenocarcinoma associated with LEGH was 25% (7/28) of the LEGH cases, 19% (7/36) when we included clinically diagnosed LEGH, and 11% (7/65) of all cases that had endocervical cells with yellow mucin.

HIK1083 latex tests were positive in 56 (88%) of the 64 patients that had endocervical cells with yellow mucin; the test was not performed in one case of AIS with PGM. Of the patients that underwent hysterectomy, 100% (28/28) of LEGH cases and 67% (eight of 12) of the PGM cases were positive for HIK1083 latex tests.

The median patient age was significantly older in cases of AIS/adenocarcinoma associated with LEGH (seven cases, median age 67 years, range 55-79 years) than in cases of LEGH without malignancy (20 cases, median age 54 years, range 37-76 years) (P < .05). The median age at the initial visit was older in cases of PGM (13 cases, median age 63 years, range 33-79 years) than in cases of LEGH (28 cases, median age 59.5 years, range 37-79 years). However, there was no significant difference between the two groups.

We investigated the preoperative cervical smears of 28 cases of LEGH with and without adenocarcinoma Table 2. We divided the smears into three types of cell clusters based on cytologic findings. Type 1 cell clusters had a honeycomb appearance or a picket fence configuration of endocervical cells with yellow mucin, bland nuclei, and distinct cell borders; this is considered characteristic findings for LEGH Image 3A. Type 2 cell clusters had a three-dimensional appearance with varicolored mucin of pink, yellow, and orange, irregular arrangement of the hyperchromatic nuclei, and occasional conspicuous nucleoli. These were atypical cells but less atypical than the appearance of adenocarcinoma cells Image 3B. Type 3 cell clusters were highly crowded clumps of atypical cells with scarce mucin, enlarged hyperchromatic nuclei, and conspicuous nucleoli that we classified as AIS or adenocarcinoma Image 3C.

Table 2

Cytologic Findings in Cases of Lobular Endocervical Glandular Hyperplasia With/Without Adenocarcinoma

AC, adenocarcinoma; AEC-GAM, atypical endocervical cells with gastric-type mucin; AIS, adenocarcinoma in situ; GMC, gastric-type mucinous carcinoma; HG, high grade; LEGH, lobular endocervical glandular hyperplasia; LG, low grade; MDA, minimal deviation adenocarcinoma; s/o, suspicious of; type 1, a monolayered sheet or a picket-fence configuration of cells with yellow mucin (Y-M); type 2, a three-dimensional cluster of cells with varicolored mucin (VC-M); type 3, a highly crowded cluster of cells with scarce mucin and nuclear atypia (S-M); UEA, usual-type endocervical adenocarcinoma.

aNo histologic relationship between LEGH and carcinoma.

Table 2

Cytologic Findings in Cases of Lobular Endocervical Glandular Hyperplasia With/Without Adenocarcinoma

AC, adenocarcinoma; AEC-GAM, atypical endocervical cells with gastric-type mucin; AIS, adenocarcinoma in situ; GMC, gastric-type mucinous carcinoma; HG, high grade; LEGH, lobular endocervical glandular hyperplasia; LG, low grade; MDA, minimal deviation adenocarcinoma; s/o, suspicious of; type 1, a monolayered sheet or a picket-fence configuration of cells with yellow mucin (Y-M); type 2, a three-dimensional cluster of cells with varicolored mucin (VC-M); type 3, a highly crowded cluster of cells with scarce mucin and nuclear atypia (S-M); UEA, usual-type endocervical adenocarcinoma.

aNo histologic relationship between LEGH and carcinoma.

Image 3

Cytologic findings of lobular endocervical glandular hyperplasia with/without adenocarcinoma. A, Type 1 cell cluster showing a picket fence configuration of endocervical cells with yellow mucin and bland nuclei. This case was postoperatively diagnosed as lobular endocervical glandular hyperplasia (LEGH) (Papanicolaou stain, ×60). B, Type 2 cell cluster showing a three-dimensional cluster displaying varicolored mucin of pink, yellow, and orange and irregular nuclear arrangement. This case was postoperatively diagnosed as minimal deviation adenocarcinoma associated with LEGH (Papanicolaou stain, ×40). C, Type 3 cell cluster showing a crowded cluster of atypical cells with scarce mucin, enlarged hyperchromatic nuclei, and conspicuous nucleoli. This case was postoperatively diagnosed as gastric-type mucinous carcinoma associated with LEGH (Papanicolaou stain, ×60).

Image 3

Cytologic findings of lobular endocervical glandular hyperplasia with/without adenocarcinoma. A, Type 1 cell cluster showing a picket fence configuration of endocervical cells with yellow mucin and bland nuclei. This case was postoperatively diagnosed as lobular endocervical glandular hyperplasia (LEGH) (Papanicolaou stain, ×60). B, Type 2 cell cluster showing a three-dimensional cluster displaying varicolored mucin of pink, yellow, and orange and irregular nuclear arrangement. This case was postoperatively diagnosed as minimal deviation adenocarcinoma associated with LEGH (Papanicolaou stain, ×40). C, Type 3 cell cluster showing a crowded cluster of atypical cells with scarce mucin, enlarged hyperchromatic nuclei, and conspicuous nucleoli. This case was postoperatively diagnosed as gastric-type mucinous carcinoma associated with LEGH (Papanicolaou stain, ×60).

We observed type 1 clusters in all cases of LEGH. We found only type 1 clusters in 18 cases for which we gave a cytologic diagnosis of AEC-GAM, low grade (AEC-GAM, LG); these patients had postoperative histologic diagnoses of LEGH. One case had type 1 and type 3 clusters, and the cytologic diagnosis was adenocarcinoma with AEC-GAM, LG. The postoperative diagnosis was UEA combined with LEGH because there was no relationship between the two components.

Two cases had both type 1 and type 2 clusters, and their cytologic diagnoses were AEC-GAM, high grade (AEC-GAM, HG). Histologically, one case revealed no obvious atypical lesions. In the other case, only one large gland had some cellular and structural atypia, and the postoperative diagnosis was atypical LEGH. Seven cases contained all three types of clusters, one of which had type 3 clusters displaying less atypia. We diagnosed that case as AEC-GAM, HG suspicious of adenocarcinoma. Four cases with type 3 clusters displaying a peripheral feathering arrangement also were diagnosed as AIS with AEC-GAM, HG. These five cases with type 3 clusters diagnosed cytologically as AEC-GAM, HG had postoperative diagnoses as AIS associated with LEGH. We diagnosed two cases with type 3 clusters that had higher nuclear and structural atypia as adenocarcinoma with AEC-GAM, HG. One was diagnosed histologically as MDA associated with LEGH, the other as GMC associated with LEGH. All cases of AIS/adenocarcinoma associated with LEGH had overlapping features of the three cluster types.

Discussion

Altered mucin expression has been associated with malignant transformation in various organs such as the pancreas, gallbladder, and stomach.21-23 Thus, mucin pattern can be a useful marker to detect cancers and precancerous lesions. In this study, we hypothesized that gastric-type mucin on Pap smears is a surrogate marker for HPV-negative endocervical adenocarcinoma and its precursors.

In the present study, we observed endocervical cells with gastric-type mucin in 0.29% of cervical smear specimens and 0.26% of endometrial specimens. This is the first study to examine the prevalence rate of endocervical cells with gastric-type mucin on Pap smear. The rate of finding AEC-GAM on cytologic smears recently has increased slightly in cervical and endometrial sampling, although this change may have been influenced by the improvement in sampling and diagnostic ability.

It is noteworthy that adenocarcinoma-associated LEGH was detected in 11% of the cases that had endocervical cells with yellow mucin. Furthermore, four of these cases developed AIS as we followed them for LEGH. These results emphasize that screening for endocervical cells with yellow mucin can provide diagnostic value, and, once LEGH is detected, continuous follow-up may be needed to detect early adenocarcinoma. Our results also indicate that LEGH has the potential to transform into cancer.

The samples of adenocarcinoma associated with LEGH in our study exhibited various cytologic forms: endocervical cells contained yellow mucin, varicolored mucin, or scarce mucin, and cell clusters showed a spectrum of nuclear and structural atypia. We regarded endocervical cells with varicolored mucin and irregular nuclear arrangements as AEC-GAM, HG, and those with less atypia and yellow mucin as AEG-GAM, LG. Atypical endocervical cells with varicolored mucin were found in cases of adenocarcinoma associated with LEGH and one case of atypical LEGH, but not in the case of UEA incidentally found with LEGH. We suggest that these cell attributes are characteristic features indicating malignant transformation of LEGH.

The present study demonstrated that endocervical cells with gastric-type mucin provides diagnostic value on cervical cytology. Consequently, we propose adding a novel category of AEC-GAM to the category of AEC and further dividing AEC-GAM into either a low- or high-grade depending on the presence of varicolored mucin and nuclear atypia. The Bethesda System for reporting cervical cytology does not include a category of endocervical cells exhibiting gastric differentiation.24 To correspond to the current Bethesda System in routine practice, it would be appropriate to classify AEC-GAM, LG as “AEC-not otherwise specified (NOS) with gastric-type mucin (GAM)” and AEC-GAM, HG as “AEC-favor neoplastic (FN) with GAM.”

According to the 2012 American Society for Colposcopy and Cervical Pathology Consensus Guidelines, colposcopy and endocervical sampling are recommended for women with categories of AEC-NOS and AEC-FN.25 However, colposcopically directed biopsy will fail to detect LEGH and adenocarcinoma associated with LEGH, because most of these lesions are typically located in the upper portion of the endocervical canal.14,26 In addition, LEGH and adenocarcinoma associated with LEGH are high-risk HPV-negative endocervical lesions and it will complicate cotesting.9,14 We recommend additional HIK1083 latex test for women with categories of AEC-GAM to confirm gastric-type mucin. MRI examination is also recommended to detect LEGH and adenocarcinoma associated with LEGH, because LEGH show a multicystic pattern.26 For clinical management of women with the categories of AEC-NOS with GAM or AEC-FN with GAM, pathologists and gynecologists need to recognize the clinicopathologic characteristics of LEGH and adenocarcinoma associated with LEGH.

There are several concerns when attempting to categorize AEC-GAM. First, it is difficult to recognize yellow mucin on liquid-based cytology because the mucin color becomes paler. Second, the cytopathologist and cytotechnologist must be trained to detect the yellow mucin. Third, adequate cervical samplings from throughout the cervical canal are required. LEGH and AIS/adenocarcinoma associated with LEGH are located in the upper portion of the endocervical canal, although HPV-positive UEA usually involves the squamocolumnar junction.14,26 In the present study, we obtained endometrial smears to look for yellow mucin.

The prevalence of adenocarcinoma with gastric differentiation will increase relative to HPV-positive adenocarcinoma as a consequence of HPV vaccination programs, and precursor lesions will not be detected by primary HPV-based screening programs.27 We recommend establishing the novel AEC-GAM category in addition to AEC-NOS and AEC-FN categories for more effective cytologic screening for HPV-negative cervical cancers.

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