Diagnostic Problems in GI Pathology
Case 6 -
Invasive Adenocarcinoma Versus Pseudoinvasion in Colonic Adenomas
Lisa Yerian, John Hart and Amy Noffsinger
The histologic assessment of colonic adenomas is frequently complicated by the interpretation of
epithelial elements in the submucosa, which may either represent benign "misplaced" epithelium of the
adenoma (also termed "pseudoinvasion") or submucosally invasive adenocarcinoma. This common diagnostic
dilemma can be quite difficult and carries huge therapeutic and prognostic implications
Benign Misplaced Epithelium, Pseudoinvasion, or Pseudo-carcinoma
Misplaced epithelium, or "pseudoinvasion," is most frequently seen in large pedunculated polyps from
the left colon, usually the sigmoid colon . The pathogenesis of this phenomenon is related to
repeated twisting and torsion of the polyp causing vascular compromise, ischemic injury, hemorrhage, and
herniation of epithelium through the muscularis mucosae into the submucosa
Pseudoinvasion is a
common finding in colonic adenomas that is clinically insignificant when accurately recognized. In
contrast, submucosally invasive adenocarcinoma is a biologically malignant lesion, carrying a risk of
lymph node or distant metastasis. The diagnosis of submucosally invasive adenocarcinoma and
its distinction from benign but dysplastic glands that are misplaced into the submucosa is thus an
important and sometimes difficult distinction with therapeutic and prognostic consequences .
In order for a colonic polyp to be biologically malignant, there must be invasion of carcinoma into
Unlike the esophagus and the stomach, intramucosal carcinoma in the colon carries
no risk of lymph node metastasis. This is attributed to the lack of lymphatic channels in the colonic
Hence, in the colon a diagnosis of invasive carcinoma indicates that tumor has invaded
through the muscularis mucosae into the submucosa.
The definitive therapy for non-malignant colonic adenomas is complete removal, if possible. In the
absence of submucosally invasive adenocarcinoma, no further therapy is required for a completely removed
colonic adenoma, irrespective of the presence of pseudoinvasion . In contrast, the presence of
submucosally invasive adenocarcinoma in a polyp carries a risk of lymph node and distant metastasis and
may therefore require further intervention. This decision is complex and requires assessment of tumor
invasion within the polypectomy specimen, completeness of excision, the histologic grade of the tumor,
and the presence of lymphatic or blood vessel invasion ,
as these factors (high-grade or poorly
differentiated tumor, presence of angiolymphatic space invasion) have been associated with an increased
risk of lymph node metastasis
The decision to pursue surgical resection depends on the estimated
risk of lymph node metastasis weighed against the risk of operative morbidity and mortality from a
surgical resection. If surgery is pursued for a completely endoscopically resected adenocarcinoma that
is well to moderately differentiated and without angiolymphatic invasion, then all parties must be aware
of the high probability that nothing will be found in the resection specimen.
Key Distinguishing Histologic Features
Architecture: The low-power assessment of the polyp may be the most
helpful histologic feature . Benign misplaced epithelium usually has a
rounded, lobular configuration, consisting of a well-circumscribed "bolus" of glands. Invasive
adenocarcinoma, on the other hand, commonly exhibits an irregular, jagged, or infiltrative profile with
angulated or poorly formed glands. Single cells or small clusters of cells without lamina propria (see
below) are features of invasive adenocarcinoma. Benign misplaced epithelium should show no architectural
features of invasive adenocarcinoma.
Epithelium: The epithelium may exhibit low-grade or high-grade dysplasia
but typically is similar to the intramucosal portion of the polyp.
Cytologically malignant cells, or higher grade cytology than that seen elsewhere in the polyp is
concerning, although not diagnostic, for invasive adenocarcinoma.
Lamina propria: The glands of benign misplaced epithelium are typically
surrounded by a rim of lamina propria that includes abundant inflammatory cells and is similar to that
seen in other, not worrisome portions of the polyp. Definite intramucosal "benign" areas of the polyp
can be extremely helpful for comparison of the stroma. Although lamina propria has a characteristic
appearance, it can vary between polyps and usually that seen in herniated glands is extremely similar to
that seen in other areas of the polyp. The stroma often contains hemorrhage and hemosiderin
importantly, there is no stromal desmoplasia . Invasive adenocarcinoma is not surrounded by lamina
propria, and stromal desmoplasia is a characteristic feature of true submucosal invasion.
Mucin pools: Benign misplaced epithelium and invasive adenocarcinoma may both be associated with
mucin pools within the submucosa
The mucin pools associated with pseudoinvasion tend to be
smooth, regular, and associated with ruptured crypts. They are either acellular or lined by dysplastic
epithelium similar to that seen at the surface of the polyp . The mucin pools of invasive
adenocarcinoma, in contrast, are irregular, jagged pools dissecting through submucosa and may contain
floating cytologically malignant cells. A practical rule regarding the nature of acellular mucin
collections is to assign the same biologic significance as that of the associated epithelium. If the
associated epithelium consists of benign misplaced glands surrounded by lamina propria, then the mucin
pools are also benign, but if the associated epithelium is cytologically malignant (like that of invasive
then the mucin pools should be regarded as part of the malignant process
Vascular invasion: The presence of true vascular invasion is not a
feature of benign misplaced epithelium and should prompt a diligent search for invasive adenocarcinoma.
In rare cases, additional deeper sections may be required to identify a small focus of invasive
What if You Can't Tell?
1. Compare the epithelium to epithelium you are confident is adenoma in the
2. Compare the stroma to stroma you are confident is the benign stroma of adenoma in the same polyp.
3. Look for evidence of definite vascular or lymphatic space invasion.
4. Cut levels. This will at least buy you a little time, and you may find more definitive evidence
of submucosal invasion in the deeper sections.
5. Show it to your colleagues.
6. Call the clinician to discuss the endoscopic findings and management plan. Benign misplaced
epithelium is extremely uncommon in sessile lesions . If the polyp was not completely excised and is
not endoscopically resectable, then the patient may need to undergo a resection irrespective of your
assessment of the submucosal epithelium. In this scenario, a diagnosis of "atypical" or "suspicious" may
7. Does immunohistochemistry help? Some investigators have attempted to utilize immunohistochemical
stains to assist in the distinction between pseudoinvasion and submucosally invasive adenocarcinoma
occurring in a colonic adenoma
Expression of stromelysin-3 was documented in invasive
carcinoma, but lack of expression did not exclude an invasive lesion . Submucosally invasive
adenocarcinomas have also been found to exhibit increased expression of the tumor suppressor gene p53 as
compared to intramucosal portions of the same polyp ,
and all of the adenomas studied (23/23)
exhibited preserved E-cadherin and collagen IV staining .
8. Occasionally a definite distinction between invasion and pseudoinvasion is not possible, and
consensus cannot be reached even among experienced GI pathologists . In these cases a descriptive
diagnosis is warranted, and a phone call to the clinician may be helpful. The pathologist may choose to
describe the finding ("deep neoplastic glands of uncertain significance"), and elaborate in a comment as
to the diagnostic problems.
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