INTRAEPITHELIAL SIGNET RING CELL CARCINOMA ARISING IN VILLOUS ADENOMA WITH HIGH GRADE DYSPLASIA

provided by Mirela Stancu, MD

Case History

A 52 year old man presented with rectal bleeding. A 1.8 cm pedunculated polyp was found in the sigmoid colon at colonoscopy. The polyp was removed using hot snare.

Microscopic Findings

The polyp was entirely submitted for histologic examination. The polyp has a villous contour composed of long, fern-like villous projections lined by high-grade adenomatous epithelium, histologic features that are diagnostic of villous adenoma with high-grade dysplasia. No intramucosal carcinoma or invasive foci into the stalk of the polyp (invasive adenocarcinoma) are noted in numerous sections and deeper levels examined. An unusual finding is the presence of frequent nodules of intraepithelial or intraluminal signet ring cells located within some of the deep and superficial adenomatous glands (see photomicrographs). The malignant cells within the nodules show variable intercellular adhesion and have the characteristic features of malignant signet ring cells: scant cytoplasm stretched over an intracytoplasmic mucin droplet, and an excentric, crescentic nucleus pushed at the periphery of the cell by the mucin vacuole. To rule out the possibility of metastatic signet ring cells, immunohistochemical stains for CK7, CK20, and CDX2 were performed. In addition, E-cadherin immunostain to evaluate for the presence or loss of this cell-adhesion molecule was performed. The signet ring cells are positive for CK20 and CDX2 and negative for CK7, immunoprofile that confirms their intestinal origin. The E-cadherin showed variable staining pattern ranging from continuous, weak membranous staining to discontinuous staining to completely absent labeling in the discohesive single signet ring cells desquamated into the luminal space. This staining pattern suggests that the loss and partial loss of E-cadherin cell-adhesion molecule may be responsible for the discohesive quality of the signet ring cells, which in turn may play a role in the tumor progression. This has been previously demonstrated in signet ring carcinoma of the stomach.

Diagnosis

INTRAEPITHELIAL SIGNET RING CELL CARCINOMA ARISING IN VILLOUS ADENOMA WITH HIGH GRADE DYSPLASIA

Discussion

Signet ring cell carcinoma (SRCC) of the colon is rare, representing less than 2% of the colonic adenocarcinomas. There are very few reports in the English literature documenting the presence of signet ring cell carcinoma within adenomatous polyps (1,2,3). Only one previous case of intraepithelial signet ring cell carcinoma within adenomatous and non-adenomatous colonic epithelium was included in a series of 19 cases of invasive signet ring cell carcinomas (1). In this study, most of the intraepithelial signet ring cell carcinoma foci were associated with invasive signet ring cell carcinoma within the same polyp or elsewhere. These reports together with the current case document the preneoplastic - neoplastic sequence for the signet ring carcinoma, which is analogous to the adenoma - carcinoma sequence of tumor progression established much earlier for the conventional adenocarcinoma of colon and rectum.

Interestingly, another case report addresses the possibility of metastatic SRCC to colonic tubular adenoma (4), emphasizing the important diagnostic role of immunohistochemical tests.

The follow-up information for SRCC arising in association with adenomatous polyps is available only in one case (2). The tumor had an invasive component into the submucosa of the stalk as well as a small residual submucosal malignant focus in the colectomy specimen (pT1N0M0). The patient was alive without evidence of metastatic disease 3 years after the surgery.

Our case did not have any evidence of invasive carcinoma, conventional type or signet ring cell type, and the immunohistochemical stains confirmed a primary intestinal origin of the tumor cells (CDX2 and CK20 positive, CK7 negative). Interestingly, some of the intraepithelial signet ring cells had discontinuous or absent membranous staining for cell adhesion molecule E-cadherin. This finding may suggest that the loss of cell adhesion molecules in SRCC may play a role in tumor progression, similar to SRCC of the stomach.

Clinically, due to the fact that the polyp was completely resected, no additional treatment was offered to the patient. Surveillance of the polypectomy site is scheduled at 2 months.

References

1. Mai KT, et al. Intestinal epithelial lesions associated with signet ring cell carcinoma of the colon and small intestine. Pathology 2002;34:51-56.
2. Tandon M, et al. Focus of signet ring cell carcinoma in an adenoma of the sigmoid colon. Arh Pathol Lab Med 1999;123:957-959.
3. Nakamura T, et al. Adenoma of rectum with multiple foci of signet-ring cell carcinoma. Dis Colon Rectum 1983;26:529-532.
4. Bismar TA, et al. Metastatic foci of signet ring cell carcinoma in a tubular adenoma of the colon. Arch Pathol Lab Med 2003;127:1509-1512

Villous adenoma with high grade dysplasia and nodules of intraepithelial signet ring cells, endoscopic snare polypectomy. Low power view of villous adenoma with branched villi lined by high-grade adenomatous epithelium (H&E, low-power view).
At the base of adenomatous villi solid nodules some with secondary lumen formation are noted (yellow arrows). H&E, low-power magnification.
At the base of adenomatous of the adenomatous glands solid nodules composed of cuboidal malignant cells admixed with signet ring cells are noted. The solid nodules are present above the basement membrane & protrude into the glandular lumen.
Large clusters of intraepithelial signet ring cells are present within the deep and superficial adenomatous glands (H&E, medium-power magnification).
Frequent intraluminal nodules of malignant signet ring cells are noted. No invasive signet ring cell carcinoma was noted in multiple sections and deeper levels (H&E, medium-power magnification).
The signet ring cells within the intraluminal and intraepithelial nodules have characteristic features: a hyperchromatic crescentic nucleus pushed at the periphery of the cell by a round mucin vacuole rimmed by scant eosinophilic cytoplasm.
The signet ring cells within the intraluminal and intraepithelial nodules have characteristic features: a hyperchromatic crescentic nucleus pushed at the periphery of the cell by a round mucin vacuole rimmed by scant eosinophilic cytoplasm.
A deep adenomatous gland contains confluent clusters of signet ring cells. The signet ring cells are distinctively located above the columnar adenomatous cells and above the basement membrane, occupying most of the luminal space.
The signet ring cells within the intraluminal and intraepithelial nodules have characteristic features: a hyperchromatic crescentic nucleus pushed at the periphery of the cell by a round mucin vacuole rimmed by scant eosinophilic cytoplasm.
The signet ring cells within the intraluminal and intraepithelial nodules have characteristic features: a hyperchromatic crescentic nucleus pushed at the periphery of the cell by a round mucin vacuole rimmed by scant eosinophilic cytoplasm.
The signet ring cells within adenomatous epithelium have increased N:C ratio and display a hyperchromatic crescentic nucleus pushed at the periphery of the cell by a mucin vacuole (HE, 40X). Many mitoses are noted.
CK 20 immunohistochemical stain highlights intraepithelial and intraluminal location of the signet ring cells.
The immunohistochemical stain for CK20 highlights the intraepithelial and intraluminal location of the signet ring cells (CK20 immunoperoxidase, medium-power magnification).
CK 20 immunohistochemical stain highlights a cluster of intraepithelial discohesive signet ring cells.
The immunohistochemical stain for CK7 fails to label any of the cells, excluding the possibility of a metastatic non-intestinal signet ring cell carcinoma (CK7 immunoperoxidase, high-power magnification).
Low power view of villous adenoma with branched villi lined by high-grade adenomatous epithelium (H&E, low-power view).
E-cadherin immunostain discontinuously labels the membranes of the signet ring cells (left) compared with the columnar cells (right) that demonstrate strong, complete membranar staining (E-cadherin immunoperoxidase, high-power magnification).
E-cadherin immunohistochemical stain discontinuously labels cell membranes of the desquamated signet ring cells (left) compared to complete membranous staining of the adenomatous columnar cells (bottom right).
Intraluminal nodule composed of signet ring cells with incomplete staining of the cell membranes with E-cadherin immunohistochemical stain.
The marker for intestinal differentiation CDX2 strongly labels the nuclei of both intraepithelial signet ring cells and the columnar nuclei of the adenomatous epithelium (CDX2 immunoperoxidase, medium-power magnification).