Introduction
Pathology interpretations are not always black and white, and shades of grey are common. For optimal patient care, it is essential that the women's health clinician and the pathologist understand each other and communicate. Clinical information is essential to the pathologist for formulating an appropriate diagnosis or differential diagnosis, and such information does not prejudice the interpretation. The pathologist needs to know whether patients have been given hormonal medications to control bleeding prior to sampling, or are on oral contraceptives, hormone replacement therapy, tamoxifen, or other hormonal medications: these all have effects on endometrial morphology. Age, menopausal status, pertinent prior surgery, and any other contributory history are also important. In turn, pathologists need to provide a report that is interpretable and clinically useful. The following discussion is provided to assist each specialty in understanding the other.
Some gynecology for the pathologist
Why is endometrial sampling performed?
There are a number of reasons. Endometrial sampling is most often performed for abnormal uterine bleeding. As part of the evaluation of infertility, it has fallen in popularity with the availability of more accurate serological tests of hormonal status. It may be warranted by a thickened endometrial stripe on transvaginal ultrasound, particularly in a postmenopausal woman. A biopsy may be performed to monitor therapy for hyperplasia, or if there is any suspicion of or a need to rule out malignancy, such as abnormal endometrial cells on a pap smear.
Abnormal bleeding may be categorized as shown in Table 1.1. In the reproductive age group, pregnancy-related causes of bleeding, including intrauterine pregnancy, ectopic pregnancy, and gestational trophoblastic disease, must always be considered. Rarely, systemic disease, such as a coagulation disorder, is the cause of abnormal uterine bleeding. Sometimes bleeding perceived as uterine by the patient is actually not of endometrial origin, or may even be nongenital, originating from the cervix, vagina, bladder, or rectum.
|
The more common etiologies in the peri- and postmenopausal woman are organic, dysfunctional and neoplastic etiologies. Organic causes of abnormal bleeding are lesions intrinsic to the uterus, such as submucous leiomyomas, adenomyosis or polyps. Abnormalities of angiogenesis are currently thought to be related to the bleeding seen with these lesions.1–3 Dysfunctional uterine bleeding is abnormal bleeding in the absence of intrinsic uterine disease, pregnancy, systemic disease, or neoplasia, and is due to hormonal irregularities. Neoplasia may be hormonally related, or hormone-independent.
Depending on the bleeding pattern and age of the patient, an endometrial biopsy or curettage may be performed as part of the evaluation of the abnormal bleeding. Postmenopausal bleeding, although often due to atrophy, must always be investigated to rule out cancer, and this often necessitates endometrial sampling. This is discussed in more detail in subsequent chapters. Other techniques employed may include transvaginal ultrasound for assessment of thickness of the endometrium. A saline sonohysterogram may be a useful adjunct to transvaginal ultrasound, as the distention of the endometrial cavity separates the anterior and posterior walls, allowing for better identification of focal lesions such as polyps. Hysteroscopy, either in office or in the hospital, allows viewing of the cavity directly as well as allowing targeted sampling.
How is endometrial sampling performed?
In-office endometrial biopsy
Due to cost and convenience, in-office endometrial sampling is often the first modality utilized when endometrial sampling is undertaken. It is usually well-tolerated by the patient, as cervical dilatation is generally not necessary. Most of the current devices available are thin plastic catheters with an internal piston that creates suction, and an opening along the catheter to allow a scraping motion and collection of tissue, such as the Pipelle device. Such devices produce a plug of tissue, or blood admixed with tissue, which can be extruded into fixative and sent for histopathological evaluation.
There have been multiple studies on the accuracy of in-office devices in the sampling of the endometrium. In general, the devices sample less endometrium than does the curettage, but they are 3accurate for diffuse lesions, although focal lesions such as polyps may be missed.4 Huang et al5 found a sensitivity of 93.8% for Pipelle and 97% for curettage for low-grade cancers, and 99.2% and 100% respectively for high-grade cancers as compared with the pathology found at final hysterectomy. Although an older study showed that a much smaller percentage of the endometrium was sampled with a Pipelle compared to a Vabra aspirator,6 in a more recent meta-analysis, the Pipelle was found to be more accurate than the Novak curette, Vabra aspirator, and a variety of lavage or cytological methods of sampling.7 Some authors report success with a Tao brush, particularly in postmenopausal women. This modality provides a cytologic rather than histologic specimen,8 however cytological endometrial sampling has not caught on in all locations. Because not all pathology laboratories may have experience evaluating cytologic endometrial specimens, discussion with the pathologist in advance of submitting such a specimen should be considered, as in any undertaking of a new method of evaluation.
Endometrial curettage
Often considered the “gold standard”, cervical dilatation and endometrial curettage with a sharp curette provides more tissue for evaluation. However it requires anesthesia and is usually performed in a hospital or (often) an ambulatory care setting, hence it increases cost.
Some pathology for the clinician
Why is a history so important?
In years past, in the USA, trainees in obstetrics and gynecology often had the opportunity to rotate through the Pathology Department of their institution during training. With the mandatory hour restrictions in training programs, this exposure has become a great deal less frequent, and so clinicians may not have a sense of how pathology works or sufficient understanding of how important a history is in making a determination. Rarely do specimens look exactly like what is in the textbooks, and the rendering of a diagnosis is often a process of developing a differential diagnosis. Lack of clinical information impedes this, and may lead to a long descriptive diagnosis rather than a concise one. As an example, the diagnoses below are both from the same specimen. In the first case, no history of exogenous progesterone therapy was provided, and in the second it was:
- Diagnosis 1 (in the absence of history): endometrial tissue irregularly developed. The glands are small and inactive. The stroma is hypercellular and focally decidualized. This may represent exogenous progestational effect. Clinical correlation suggested.
- Diagnosis 2 (with history): benign endometrium, with glandular and stromal features consistent with progestin effect.
How does the pathologist evaluate tissue?
Gross Evaluation
Tissue is first examined grossly (by eye), and described in the report. The description generally includes whether the tissue was received fresh or in fixative, and the appearance of the tissue, including weight (for hysterectomies), size of the tissue or measurement in aggregate (for endometrial sampling), and appearance of the tissue. This is useful in cases where there is a discrepancy in the amount of tissue the clinician thinks was obtained, and what is seen on the slide. In some endometrial samples, most of what is in the device is actually blood, and this may give the clinician a false impression of abundant tissue. If the contents are ejected into formalin, this plug of tissue and blood may hold its shape, making it appear as though more tissue is there than is actually present. Rarely, tiny pieces of tissue either do not make it from the sampling device to the jar or get lost in processing in the pathology laboratory; the gross description can provide useful information here for comparison.
For larger resections, the gross description may give the distance of a visible tumor from margins, and the number, size, and character of any dissected lymph nodes for cancer procedures. If a microscopic assessment of margin status will be needed, ink may be applied to the specimen, so that the margins can be appreciated microscopically. This should all be reflected in the gross description portion of the pathology report.
The summary of sections lists what tissue was submitted to make the slides. In the case of a biopsy, generally all of the tissue is submitted, and is so stated. In a larger resection, submission of all the tissue is not practical, and representative sections are submitted. The summary of sections localizes the slides to where the tissue was taken from.
A typical gross description of an endometrial biopsy and a hysterectomy for uterine leiomyomata are given in the boxes below:
Microscopic examination
After gross examination of the tissue, selected tissue (for larger specimens) or biopsy tissue is placed inside a plastic tissue cassette labeled with the case number. This cassette is placed in formalin and goes through a series of dehydration steps in different solutions. My laboratory has computerized processors that change the solutions on a fixed time schedule. Depending on the types of cases seen, a laboratory may have a processing machine dedicated to “rush” cases, with shorter processing time. Because the processing goes along a specific schedule, missing a cutoff time means a case cannot be appropriately processed and has to wait until the next run. Thus, it is important for clinicians to be aware that there are times tissue can be rushed for the same day and other times when this may not be possible. A telephone call to the pathologist discussing the nature of the problem and the reason for the rush is often helpful in these instances. The request for a “rush” on a specimen should be a judicious one.
After the tissue has been processed and is dehydrated, it is removed from the plastic cassette and embedded in paraffin on the outside of the cassette, creating a tissue block. The tissue block is placed on a microtome, a device that allows extremely thin slices to be cut from the block, approximately 4.5 μm. Hence, many slices can be cut from a single block, up to 50–100, depending on the size of the tissue. The microtome produces ribbons of tissue, multiple slices in series, which are floated on a warm water bath, picked up onto glass slides, stained, cover-slipped, and labeled. If duplicate slides are needed 6for performing special stains such as immunohistochemistry or for outside consultation, they can be recut from the block. If a tiny area suggests that there is more of a lesion in the block to be evaluated, levels can be cut. Levels differ from recuts, which are the next adjacent section. Levels are cut beyond a “skip area” between the previous slide and the next one, with the aim of identifying a lesion further into the block (Figures 1.1 and 1.2).
Laboratories are required to keep slides and tissue blocks for a number of years, which may vary by laboratory location. This is important if future studies or evaluations are needed.
Pathology reports
In addition to patient demographics, the requisition slip should also contain the source of the specimen, the procedure that was performed, and any clinical information that is relevant, including any prior hormonal therapy, last menstrual period or menopausal status, pertinent prior surgery, working diagnosis, etc.
7These will be entered onto the final pathology report, along with the gross description, and final diagnosis. A specific microscopic description of what is seen is included in the report by some laboratories but not by others. Also sometimes included are specific comments by the pathologist, focusing on key diagnostic features or recommendations. This is also often where results of additional testing, such as immunohistochemistry, cytogenetics, or molecular diagnostics are reported.
A question that comes up at times is whether or not to put multiple biopsies in the same jar. This is more relevant to cervical than endometrial biopsies. There is a separate charge for each jar, and a separate diagnosis on the report. It would not be advisable to put an endometrial curettage and an endocervical curettage in the same jar, as separate information will not be possible, and the endocervical component, if scanty, may be overlooked. For hysterectomies with lymph node sampling, laterality or localization of the nodes may be important clinically, and hence separate jars should be used. The bottom line is that if separate diagnoses are needed, separate jars should be used.
Separate final diagnoses are provided in the pathology report for each separate specimen jar. If more than one diagnosis is given for a specimen, they are usually stated in descending order of importance. For cancer resections, (not biopsies), the pathologic TNM classification is often provided as pTNM, to distinguish it from the clinical staging. Terminology for neoplasms usually corresponds to World Health Organization terminology, however it may be variable; this is discussed in the following chapters under specific diagnoses.
If additional stains or levels are obtained, this highlights that a case is more complicated, and perhaps a more difficult differential diagnosis. It will also increase the turnaround time, and may add extra charges to a case. Pathology is a consultative specialty, and cases are often shown to colleagues in the department by the pathologist, and may be sent out for a second or expert opinion in difficult cases. These consultations are generally referenced in the report as well.
A pathology report should be concise, unambiguous, and keyed to current terminology and guidelines for reporting. A clinician should never hesitate to call the pathologist to discuss or explain a report. Such conversations optimize patient care, and are educational on both sides.
Adequacy of specimen
With liberal use of in-office endometrial sampling, the problem of specimens that show only scant superficial endometrial glandular strips on histology has become common9 (Figure 1.3). In the setting of a sample from a postmenopausal woman who has a thin endometrial stripe on ultrasound, this may reflect genuine atrophy; however, it may also reflect insufficient sampling of a nonatrophic uterine cavity.
Figure 1.3: Pipelle sampling.
(a) Low power view of a Pipelle sample showing what appears to be much tissue, but is actually mostly blood. (b) Strips of benign endometrial glands from pipelle sampling on a recently postmenopausal woman.
The way a report is phrased in these cases is variable. Concern has been raised by some about calling such a specimen “inadequate”, as it may be taken as reflecting poor sampling technique, having medicolegal connotations.10 A statement such as “extremely scanty strips of endometrial glands insufficient for further evaluation” conveys what is present, and allows clinical correlation as to whether sampling was adequate, which is necessary to make this determination. Any atypia should be reported. The presence of mitotic activity, pseudostratification, or tubal metaplasia suggests at least some estrogenic influence (Figures 1.4–1.7). While this may not be significant in a recently menopausal woman, it may be of concern in a woman many years remote from the onset of menopause. Clinical judgment is important in these cases, and needs to be correlated with the findings.
Figure 1.4: Endometrial glandular strips from a biopsy.
Presence of pseudostratification and mitosis (arrow) confirm estrogenic effect.
Figure 1.6: Papillary fragments on an endometrial biopsy.
This may or may not represent significant pathology, but needs to be reported and evaluated further.
These strips sometimes assume a pseudopapillary architecture, and this should not be interpreted as a papillary lesion10.
A variety of conditions may lead to scant tissue, including atrophy, hormonal therapies that suppress the endometrium (such as leuprolide acetate or progestins), prior heavy bleeding, prior curettage, Asherman's syndrome, cervical stenosis, or operator inexperience. Abundant tissue is more likely when there is abundant endometrium present, such as late proliferative endometrium, secretory endometrium, pregnancy-related changes, estrogenic therapy, or hyperplasia/neoplasia.
References
- Stewart EA, Nowak RA. Leiomyoma-related bleeding: a classic hypothesis updated for the molecular era. Hum Reprod Update 1996;2:295–301.
- The ESHRE Capri Workshop Group. Endometrial Bleeding. Hum Reprod 2007;13:421–31.
- Hickey M, Fraser I. Human uterine vascular structures in normal and diseased states. Micros Res Tech 2003;60:377–89.
- Revel A. Multitasking human endometrium. A review of endometrial biopsy as a diagnostic tool, therapeutic applications, and a source of adult stem cells. Obstet Gynecol Survey 2009;64:249–57.
- Huang GS, Gebb JS, Einstein MH, Shahabi S, Novetsky A, Goldberg GL. Accuracy of preoperative endometrial sampling for detection of high-grade endometrial tumors. AJOG 2007;196:243.e1–5.
- Rodriguez GC, Yaqub N, King ME. A comparison of the Pipelle device and the Vabra aspirator as measured by endometrial denudation in hysterectomy specimens: the Pipelle device samples significantly less of the endometrial surface than the Vabra aspirator. Am J Obstet Gynecol 1993;168:55–59.
- Dijkhuizen FP, Mol BW, Brolmann HA, Heintz AP. The accuracy of endometrial sampling in the diagnosis of patients with endometrial carcinoma and hyperplasia. Cancer 2000;89:1765–72.
- Williams ARW, Brechin S, Porter AJL, Warner P, Critchley HOD. Factors affecting adequacy of Pipelle and Tao Brush endometrial sampling. BJOG 2008;115:1028–36.
- McCluggage WG. My approach to the interpretation of endometrial biopsies. J Clin Pathol 2006;59:801–12.
- McCluggage WG. Miscellaneous disorders involving the endometrium. Semin Diagn Pathol 2010;27:287–310.