Lymph node metastases of carcinoma associated with abundant mucin that may be intra- or extracellular.

The term metastatic signet ring cell adenocarcinoma is used for neoplasms with abundant intracellular mucin. Metastatic mucinous carcinoma and colloid carcinoma are terms used for neoplasms with abundant extracellular mucin.

Metastatic malignant neoplasms of undetermined origin are a difficult and often frustrating problem. In this group, which represents approximately 1% to 2% of all patients with metastatic malignancy, adenocarcinomas are, by far, the most common, accounting for over half of all cases (1). Mucin secretion is common in adenocarcinomas and can often be identified as intra-cytoplasmic minute droplets using mucicarmine or periodic acid–Schiff (PAS) with diastase stains. A much smaller subset of adenocarcinomas has abundant mucin, and these tumors can be divided into two general types: signet ring cell (adeno)carcinoma and mucinous (adeno)carcinoma. In signet ring cell carcinoma, mucin is mainly intracellular, and the cells characteristically have abundant clear cytoplasm displacing and indenting the nucleus to one side. Although signet ring cells can be identified as a minor component of adenocarcinomas, the term signet ring cell carcinoma is used when a substantial number of signet ring cell carcinoma cells are present. In mucinous carcinoma, the mucin is mainly extracellular, accumulating in large pools in the surrounding tissues, and representing over 50% of the total tumor mass. Both of these types of adenocarcinoma can arise at virtually any anatomic site from which adenocarcinomas can arise. However, these histologic types of adenocarcinoma are more frequent in certain organs. Approximately 95% of signet ring cell carcinomas arise in the stomach, breast, colon, lung, and prostate (2,3,4). Of these, the relative frequency of signet ring cell carcinoma is highest in the stomach, where it represents approximately one-third of all cases. The relative percentage of signet ring cell carcinoma at other sites is much lower.

Signet ring cell carcinoma of the stomach, also known historically as the diffuse type of gastric carcinoma as well as linitis plastica, represents approximately one-third of all gastric carcinomas. The median age of patients with all types of gastric adenocarcinoma is 50 years; however, signet ring carcinomas represent a disproportionately higher percentage of neoplasms in younger patients (5). The risk factors known for gastric carcinoma, including geographic distribution, environmental factors, and Helicobacter pylori infection apply mostly to the intestinal-type and not to signet ring cell carcinoma (5). Signet ring cell carcinomas are clinically more often aggressive than intestinal-type neoplasms and/or are diagnosed at later clinical stage and thus have a poorer prognosis. Signet ring carcinoma tends to arise in the prepyloric area of the stomach, and obstruction can occur as the neoplasm infiltrates and thickens the gastric wall. These neoplasms initially spread to perigastric lymph nodes, and prognosis correlates both with the location of the lymph nodes involved and the number of lymph nodes involved (1 to 6, 7 to 15, and more than 15). The classification based on the number of lymph nodes involved is more reproducible (6,7).

Signet ring cell carcinoma of the breast, in pure form, is a rare type of breast carcinoma. In one study, Hull and colleagues identified pure signet ring cell carcinoma in four of 535 (0.7%) cases of breast cancer (8). However, signet ring cells can occur as a minor component of breast carcinomas of both ductal and lobular type (more commonly in lobular carcinomas), and an appreciable percentage of signet ring cells are associated with poorer prognosis in patients with lobular carcinoma. Cutoffs of greater than 10% or 20% signet ring cells have been used by others to support the diagnosis of signet ring cell variant of lobular carcinoma (9,10). In lymph nodes, metastases of lobular carcinoma can have many more signet ring cells than that seen in the primary breast neoplasm.

The most common sites of mucinous carcinoma are the gastrointestinal tract, pancreas, breast, ovary, and prostate (11,12,13). In the gastrointestinal tract, the order of frequency from high to low is: colon and rectum, stomach, ileum, and anal canal. Mucinous carcinoma of the colon and rectum is more frequent in younger patients, and reportedly is clinically more aggressive than typical adenocarcinomas arising at this site (11,13). In the appendix, colon, and rectum, mucinous carcinomas can be associated with chronic ulcerative colitis (13). In the anus, mucinous carcinomas may arise from the glandular crypts in the upper anal canal, from anal glands, and particularly from chronic fistulous tracts in Crohn disease (14). Mucinous carcinomas tend to have a bulky gross appearance, with rounded borders, soft consistency, glistening cut surfaces, and cystic structures oozing a grayish, gelatinous substance (11,12,13). Mucinous colonic carcinomas are prone to wide dissemination, even small primary tumors (16).

In the breast, mucinous carcinoma constitutes approximately 2% of all invasive breast tumors (17). These neoplasms are more common in older women, the incidence of lymph node metastases is low, and affected patients generally have a better prognosis (17,18). In the prostate, recognition of mucinous carcinoma is clinically important because of its aggressive biologic behavior and poor response to hormone treatment (19).