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2008 —June Case of the Month

Updated July 1, 2008

CLINICAL SUMMARY: CECUM  

CAP Foundation June 2008 Online Case of the Month

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After reading the summary, try answering the three related multiple-choice questions below.

A 65-year-old woman, who had a modified radical mastectomy performed 3 years earlier for breast carcinoma, presented with abdominal distension and altered bowel habits. Following CT-scan of the abdomen and upper and lower GI endoscopy, a colonic biopsy was performed, showing adenocarcinoma with a MUC1(-), ER(-), CDX2(+), CK7(-) and CK20(+) imunophenotype.

The patient developed small intestinal obstruction and a right-hemicolectomy was performed. A right hemicolectomy specimen revealed a circumferential stenosing tumor involving the cecum and the proximal ascending colon. The longitudinal axis of the tumor measured 6.5 cm and the tumor thickness was 2.5 cm.

Archive Case and Diagnosis: This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2005, Case 06 and is a Signet-ring cell carcinoma, primary.

Criteria for Diagnosis and Comments:
Primary signet-ring cell carcinoma is a rare but distinct variant of colorectal adenocarcinoma. In a series of 5,350 colorectal cancer cases from Memorial Sloan Kettering Hospital between 1986 and 1997, 46 cases (1%) were identified as signet-ring cell carcinoma1 and a review of 3,690 cases of colorectal carcinoma from Roswell Park Cancer Institute identified 29 patients (0.8%) with signet-ring cell carcinoma.2 This histologic variant is more common in patients with chronic ulcerative colitis, with up to 30% of colon cancers occurring in this setting being signet-ring cell type.3 Signet-ring cell carcinoma also appears to occur at a younger age than the more common variants of colorectal carcinoma.4

The typical signet-ring cell has a single large mucin vacuole displacing the nucleus to the cell periphery. In the present case the signet-ring cell carcinoma occurs in association with abundant pools of extracellular mucin. According to the current World Health Organization (WHO) criteria,5 greater than 50% of the tumor must be represented by signet-ring morphology to warrant being placed in this classification category and this feature supersedes the presence of extracellular mucin.3

In most cases signet-ring cell carcinomas are large and barrel shaped. A report of the CT findings in one series indicated that circumferential concentric thickening and a target appearance was typical.6 Most colonic signet-ring cell carcinomas are associated with abundant extracellular mucin, as in this case, and only a minority (up to 20%) have the classic gross morphology seen in the stomach, namely a diffuse infiltrative scirrhous appearance (linitis plastica). Signet-ring cell carcinomas may be found anywhere in the colon and rectum but are relatively more frequent among proximal carcinomas.

Signet-ring cell carcinomas and mucinous adenocarcinomas in general are usually diagnosed at a more advanced stage than other colorectal carcinomas. Common presenting complaints include bleeding and bowel obstruction. When patient outcomes are compared with other colorectal carcinomas of identical stage, a poorer survival rate is still evident.1 Lymphatic space invasion may be prominent in signet-ring cell carcinomas, as in the present case. A characteristic feature of those cases with adverse outcomes is peritoneal dissemination and, as is the case with advanced gastric signet-ring cell carcinoma, liver metastases are relatively infrequent.1,2,4

Signet-ring cell carcinomas of the colon are phenotypically akin to poorly differentiated and mucinous carcinomas and, especially when proximally located, are apt (30%) to show acquired microsatellite instability7 due to epigenetic inactivation of hMLH1. In younger patients with this type of tumor, particularly those with a family history of colorectal carcinoma, consideration should be given to genetic studies to exclude Hereditary Nonpolyposis Colorectal Carcinoma (HNPCC). Frequent loss of expression of E-cadherin, a transmembrane glycoprotein that mediates calcium-dependent intercellular adhesion, is a common finding in breast and gastric carcinomas of this phenotype and has also been reported in colorectal signet-ring cell carcinomas. In some cases this has been shown to be due to inactivation of the E-cadherin gene by methylation of CpG islands located in the gene's promoter region.8 K-ras mutations, which occur in up to 50% of colorectal carcinomas overall, are usually not found in signet-ring cell carcinoma.7

High grade neuroendocrine carcinomas of the colon and rectum are quite rare but some reported examples have exhibited a signet-ring phenotype. Goblet cell carcinoids, on the other hand, which have low grade malignant behavior, are encountered almost exclusively in the appendix but occasionally occur at other sites. Extension of the tumor from the appendix into the cecal wall is not an uncommon event, however, and can present at endoscopy as an area of induration suggesting a cecal primary. Histologically this tumor consists of nests of cells that have a goblet cell or signet-ring cell morphology and extracellular mucin is often present; smaller populations of cells with crypt neuroendocrine or Paneth cell differentiation are also typically represented.9

Given the rarity of signet-ring cell carcinomas of the colon and the frequent association of this phenotype with the stomach, and, less commonly, other sites such as breast, lung and prostate, the question frequently arises on biopsy whether the colonic tumor may represent a metastasis. Lung and prostate primary sites can be distinguished by expression of TTF and PSA respectively. Goldstein, et al.10 compared the immunophenotype of a series of gastric and colonic signet-ring cancers and concluded that both showed a cytokeratin profile similar to their glandular counterparts; a colonic primary is supported if the neoplastic cells have a cytokeratin7(-) / cytokeratin20(+) staining pattern, whereas a gastric primary by the converse, cytokeratin7(+) / cytokeratin20(-) profile. Others,11 however, have found considerable overlap in the cytokeratin profiles among signet-ring cell carcinomas from these two sites.

Chu and Weiss11 compared the immunophenotypic profiles of breast, gastric and colonic signet-ring cell carcinoma using a battery that included antibodies to several mucin core proteins or apoproteins (MUC1, MUC2, MUC5AC), CDX-2, a transcription factor related to gastro-intestinal differentiation and HepPar 1, an antibody to a hepatocyte derived antigen. Breast signet-ring cell cancers showed several differences in staining from colon and gastric primaries including CDX-2(-), ER(+) and MUC1(+). CDX-2 nuclear staining was more prominent in colonic signet-ring cell carcinomas and HepPar1 in gastric; about half of the gastric cases expressed MUC2 and MUC5AC whereas virtually all cases of colon signet-ring cell carcinoma expressed them. The authors concluded that to distinguish signet-ring cell carcinomas of gastric from those of colonic origin, HepPar 1 positivity and heterogeneous CDX-2 staining strongly favors a gastric primary site, whereas HepPar 1 negativity along with diffuse and homogeneous CDX-2 nuclear positivity and diffuse cytoplasmic MUC2 and MUC5AC positivity strongly favors a colonic primary site.

Supplementary Questions For each of the following, select the most likely diagnosis from the diagnostic set (an answer may be used once, more than once, or not at all).

Question Diagnostic Set
1. Which of the following molecular events has been most specifically associated with decreased cellular adhesion and diffuse infiltration, characteristic of signet-ring carcinoma? A.  hMLH1 inactivation
B.  K-ras mutation
C.  E-cadherin inactivation
D.  Microsatellite instability
E.  APC mutation
2. Which primary site is favored by the following immunohistochemical profile exhibited by a metastatic signet-ring carcinoma: CDX2(+), MUC1(-), MUC2(+), MUC5AC(+), CK7(-), CK20(+), TTF(-), PSA(-)? A.  Lung
B.  Breast
C.  Prostate
D.  Colon
E.  Stomach
3. Which of the following statements is true of colorectal signet-ring cell carcinoma? A.  The most common histologic variant of carcinoma involving the cecum.
B.  Occurs in an older age group than other histologic variants of colorectal carcinoma.
C.  In advanced disease is more often associated with peritoneal dissemination than with liver metastases.
D.  Has a better prognosis, adjusted for stage, than non-mucinous carcinoma of the colorectum.
E.  Is typically associated with a diffuse infiltrating scirrhous appearance.

References

  1. Nissan A, Guillem JG, Paty PB, Wong WD, Cohen AM. Signet-ring cell carcinoma of the colon and rectum: a matched control study. Dis Colon & Rectum. 1999;42:1176-1180.
  2. Anthony T, George R, Rodriguez-Bigas M, Petrelli NJ. Primary signet-ring cell carcinoma of the colon and rectum. Ann Surg Oncol. 1996;3:344-348.
  3. Redston M. Epithelial Neoplasms of the Large Intestine, Chapter 19, In: Odze RD, Goldblum JR, Crawford JM, eds. Surgical Pathology of the GI Tract, Liver, Biliary Tract, and Pancreas. Philadelphia: Saunders;2004:441-472.
  4. Tung SY, Wu CS, Chen PC. Primary signet ring cell carcinoma of colorectum: an age- and sex-matched controlled study. Am J Gastroenterol. 1996,91:2195-2199.
  5. Hamilton SR, Vogelstein B, Kudo S, et al. Carcinoma of the Colon and Rectum In: Hamilton SR, Aaltonen LA, eds. Pathology and Genetics, Tumours of the Digestive System. Lyon: IARC Press; 2000:105-119.
  6. Kim HJ, Ha HK, Cho KS et al. CT features of primary colorectal signet-ring cell carcinoma. J Comput Assist Tomogr. 2001,25:225-230.
  7. Kanazawa T, Watanabe T, Kazama S, et al. Poorly differentiated adenocarcinoma and mucinous carcinoma of the colon and rectum show higher rates of loss of heterozygosity and loss of E-cadherin expression due to methylation of promoter region. Int J Cancer. 2002;102:225-229.
  8. Kawabata Y, Tomita N, Monden T, et al. Molecular characteristics of poorly differentiated adenocarcinoma and signet-ring-cell carcinoma of colorectum. Int J Cancer. 1999;84:33-38.
  9. Carr NJ, Arends MJ, Deans GT, Sobin LH. Adenocarcinoma of the Appendix In: Hamilton SR, Aaltonen LA, eds. Pathology and Genetics, Tumours of the Digestive System. Lyon: IARC Press; 2000:95-98.
  10. Goldstein NS, Long A, Kuan SF, Hart J. Colon signet ring cell adenocarcinoma: immunohistochemical characterization and comparison with gastric and typical colon adenocarcinomas. Appl Immunohistochem Mol Morphol. 2000;8:183-188.
  11. Chu PG, Weiss LM. Immunohistochemical characterization of signet-ring cell carcinomas of the stomach, breast, and colon. Am J Clin Path. 2004;121:884-892.