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What is dysplasia?

If histologic analyses of biopsies obtained from the esophagus are interpreted or read by the pathologist as Barrett's esophagus (specialized intestinal metaplasia of the esophagus), the pathologist then looks for changes in the Barrett's tissue referred to collectively as dysplasia. Dysplasia, or dysplastic changes, are atypical changes in the nuclei of cells (the inside of the cell that contains DNA), the cytoplasm (the portion of the cell surrounding the nuclei), or in the growth pattern of cells. These changes can be subtle or very pronounced. They are considered pre-cancerous changes (increases the risk of developing cancer). Barrett's biopsies are usually reported with readings of "negative for dysplasia", "indefinite for dysplasia", "low-grade dysplasia" and "high-grade dysplasia". Sometimes terms such as "mild dysplasia" or "severe dysplasia" are used, but these terms are no longer widely accepted by expert gastrointestinal pathologists.

Negative for dysplasia
This means that there are no atypical changes in the Barrett's tissue. The growth pattern of the cells is very even with the cells lined up in a neat row. The nuclei (center of the cell) are not large and do not have prominent nucleoli (dark spots in the nucleus). The cytoplasm appears normal.

Barrett's esophagus, negative for dysplasia
Microscopic photo: Barrett's esophagus, negative for dysplasia
The surface cells are lined up in an even row. The nuclei of the cells are normal appearing and neatly lined up along the basement membrane. The dark blue cells are Alcian blue staining goblet cells.

Photo courtesy of Robert Odze - Brigham & Women's Hospital - Boston

Indefinite for dysplasia
This is an intermediate reading between negative and low-grade dysplasia. It simply means that the pathologist is not certain whether changes seen in the tissue are due to dysplasia. For example, esophagitis (inflammation of the lining of the esophagus from acid injury) can make cells look atypical so that they resemble dysplastic cells although they are not dysplastic. The pathologist may see other signs of inflammation in the biopsy to help distinguish between inflammatory changes in the tissue and true dysplasia. Sometimes a pathologist may determine that dysplasia is difficult to grade due to inflammation.

Low-grade dysplasia
This means that there are some atypical changes but these changes do not involve most of the cells, and the growth pattern of the glands is still normal. In "low-grade dysplasia" some of the nuclei, less than 50%, are large and have dark spots but the cells are still growing in an even row. Some cells are dividing (a process called mitosis which usually indicates increased growth rate), but very few.

High-grade dysplasia
This is considered the most advanced dysplasia with atypical changes in many of the cells and a very abnormal growth pattern of the glands. In high-grade dysplasia, the growth pattern of the glands, or rows of cells, are distorted or very irregular. Some of the glands are branching or budding. More than 50% of the cells have large spotted nuclei and are frequently dividing. The number of Alcian blue staining goblet cells is reduced. The cellular cytoplasm is reduced and looks abnormal.

Microscopic Photo of Barrett's Esophagus - High Grade Dysplasia
Microscopic photo: Barrett's esophagus, high-grade dysplasia
The surface cells are NOT in neat, even rows. The nuclei are large and the glands are distorted. None of the Barrett's cells are in the lamina propria and therefore this is not cancer. The small cells seen in the lamina propria are inflammatory cells and normal stromal cells.
Photo courtesy of Robert Odze - Brigham & Women's Hospital - Boston

Some pathologists call high-grade dysplasia "carcinoma in situ" because the changes in the cells and growth pattern of the cells resemble those of cancer cells. The difference between "carcinoma in situ" and cancer is that, in "carcinoma in situ", the pathologist has made the judgment that all of the cells are still confined to the basement membrane and have not migrated into or invaded the lamina propria. In the diagnosis of early cancer, the pathologist has made the judgment that cells have migrated below their basement membrane and into the lamina propria.

Important Tip: Carcinoma In Situ

Microscopic Photo of a Barrett's Cancer
Microscopic photo: A Barrett's associated cancer (lamina propria)
This is a magnified view of the lamina propria in a biopsy from Barrett's esophagus. Cancer cells can be seen scattered within the lamina propria, below the normal boundary of their basement membrane.
Photo courtesy of Robert Odze - Brigham & Women's Hospital - Boston

Variation in the interpretation of dysplasia

There are problems with the consistency of readings of dysplasia and therefore, problems determining a patient's risk of developing cancer based on these readings. Ideally, all pathologists viewing the same slide would grade the dysplastic changes exactly the same. Unfortunately, this is not the case. Although there is good agreement in the interpretation of high-grade dysplasia and cancer among EXPERT GI pathologists, there is much less agreement in the interpretation of the other categories of dysplasia.

Dysplasia and cancer risk

At the present time, the clinical management of patients who have Barrett's esophagus is based almost solely on the histologic readings of their endoscopic surveillance biopsies. Patients who have readings of "negative for dysplasia" are considered to be at low-risk for developing cancer.

"High-grade dysplasia" is the diagnosis most widely used to identify a group of Barrett's patients who are at increased risk of developing adenocarcinoma of the esophagus, but not all patients who have high-grade dysplasia develop cancer. There have been two large studies of patients with high-grade dysplasia followed for many years. One study followed more than 1,000 patients who had Barrett's esophagus over a course of 20 years. Patients who were diagnosed with high-grade dysplasia and followed by the researchers for more than a year before developing cancer, had only a 15% chance of developing cancer over an 8 year period. Another study of more than 300 patients reported that the chance of developing cancer over a 5 year period was 59% in patients who already had high-grade dysplasia when they entered the study and 31% in those patients who developed high-grade dysplasia after they entered the study. Smaller studies have also reported cancer developing in a variable number of patients with high-grade dysplasia, ranging from 14-56%. The reasons these numbers are so variable are unknown but may be related to differences in patients. One of these differences may be that patients who enter a study with a diagnosis of high-grade dysplasia may be further along in their time course to the development of cancer and therefore may develop cancer sooner than patients who developed high-grade dysplasia later during a study. It also may be due to differences in how the pathologists at these various medical centers read dysplasia. There may be other factors as well. One study reported that patients who had only a small area of high-grade dysplasia in one biopsy had much less of a chance of developing cancer compared to those who had a greater area of dysplasia or dysplasia in multiple biopsies, but these findings were not confirmed by another study. Although the numbers of patients with high-grade dysplasia who eventually develop cancer varies among medical centers, what is important to know is that MANY PATIENTS WHO HAVE HIGH-GRADE DYSPLASIA DO NOT PROGRESS TO CANCER DURING LONG-TERM FOLLOW-UP and the numbers of those who do may be much lower than originally thought.

Agreement in the diagnosis of high-grade dysplasia and cancer is good among experienced GI pathologists, but it may not be as good in the hands of pathologists less experienced in reading Barrett's biopsies. Many pathologists do not get much experience reading these biopsies because high-grade dysplasia is not a common diagnosis and there is not the opportunity to see many cases. It is widely recommended that Barrett's biopsy readings of high-grade dysplasia be confirmed by an experienced GI pathologist and that the patient undergo a second endoscopy with biopsy before any treatment of high-grade dysplasia is recommended. Also, because most gastroenterologists do not have the opportunity to take care of many Barrett's patients with high-grade dysplasia, it is preferable that these patients be referred to a large specialty center with esophageal surgeons and gastroenterologists experienced in the management of high-grade dysplasia.

Although it is well accepted that readings of high-grade dysplasia does identify a group of patients with Barrett's esophagus who are at increased risk for cancer, readings of low-grade dysplasia have been much less useful in the prediction of who will develop cancer. In part, this may be due to the disagreement among pathologists in the interpretation of low-grade dysplasia. 

Other tests, in addition to histology, are needed to better separate those patients who will go on to develop cancer from those who will not. There are many studies looking at different tests to determine who with Barrett's esophagus will, or will not, go on to get cancer. Some studies have shown that one test, called flow cytometry, can be combined with histology to better separate Barrett's esophagus patients into those who are at increased risk of developing cancer from those who are not.

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