Lower Gastrointestinal Tract and Microsatellite Instability (MSI)

Abstract

By conventional definition, the lower gastrointestinal (GI) tract includes the appendix, entire colon, and anus. Diseases involving these organs are traditionally classified into nonneoplastic and neoplastic categories. Clinical application of immunohistochemistry (IHC) is most useful in the diagnosis of neoplastic lesions, with a few exceptions such as to identify of viral pathogens in infectious colitis and to facilitate diagnosis of Hirschsprung’s disease. For diagnosis of neoplasm, IHC is particularly useful in several aspects: (1) to help confirm glandular dysplasia associated with inflammatory bowel disease (IBD) and to differentiate it from sporadic adenoma in challenging cases; (2) to confirm diagnosis and grade of neuroendocrine tumors; (3) to confirm diagnosis of a poorly differentiated or undifferentiated colonic adenocarcinoma variant, such as medullary carcinoma; (4) to help differentiate commonly encountered benign and malignant primary mesenchymal tumors; (5) to differentiate primary carcinomas from various morphological mimickers from other organ systems, such as carcinomas of the gynecological and genitourinary systems; and, (6) to initiate Lynch syndrome screening in patients with diagnosed colorectal cancer.

In this chapter, we provide an overview of the most useful markers in the diagnosis of lower GI tract diseases, albeit many of them are shared with the upper GI chapter. The content is organized into 19 diagnostic issues frequently encountered in daily practice. The use of both individual markers and other relevant markers to form effective panels to address specific diagnostic challenges are illustrated in a tabular format. Concise notes with representative microscopic pictures are included whenever deemed necessary.

Frequently Asked Questions

Overview

• 1. Staining patterns of commonly used markers in normal colonic mucosa (Table 29.1)

• 2. Staining patterns of commonly used markers in usual colorectal adenocarcinoma (Table 29.2)

Appendix

• 3. Markers helpful in differentiating common benign glandular proliferative lesions involving the appendix (Table 29.3)

• 4. Useful markers differentiate goblet cell adenocarcinoma, classic neuroendocrine tumor, and conventional adenocarcinoma with signet ring cells (Table 29.4)

• 5. Markers to distinguish mucinous tumors of appendiceal versus ovarian origin (Table 29.5)

Colon and Rectum

• 6. Commonly used markers for diagnosis of Hirschsprung’s disease and potential pitfalls (Table 29.6)

• 7. Different staining patterns between usual colorectal adenocarcinoma and some of its unique variants (Table 29.7)

• 8. Markers to differentiate colorectal adenocarcinoma from metastatic adenocarcinomas of the breast, pancreas, and lung (Table 29.8)

• 9. Markers to differentiate colorectal adenocarcinoma from common gynecological carcinomas (Table 29.9)

• 10. Markers to differentiate colorectal adenocarcinoma from primary adenocarcinoma of the bladder, urachus, and prostate (Table 29.10)

• 11. Markers to differentiate colorectal adenocarcinoma from peritoneal mesothelioma (Table 29.11).

• 12. Markers to distinguish well-differentiated neuroendocrine tumors (WD-NETs) of colorectal origin versus other organ systems (Table 29.12)

• 13. Markers to differentiate common colonic mucosal mesenchymal polyps (Table 29.13)

• 14. Markers to differentiate common primary mesenchymal tumors of the colon and rectum (Table 29.14)

• 15. Markers useful to confirm dysplasia in inflammatory bowel disease (IBD) and to differentiate IBD -associated dysplasia from sporadic adenoma (Table 29.15)

• 16. Mismatch repair (MMR) proteins markers and algorithm to assess the risk of Lynch syndrome (Table 29.16)

Anus

• 17. Markers to differentiate adenocarcinoma of anal duct origin from small intestinal, colorectal adenocarcinoma, endocervical, and prostatic adenocarcinoma (Table 29.17)

• 18. Markers for anal Paget’s disease versus melanoma in situ (Table 29.18)

• 19. Markers for anal squamous carcinoma versus basal cell carcinoma versus urothelial carcinoma versus small cell carcinoma (Table 29.19)

Table 29.1 Staining patterns of commonly used markers in normal colonic mucosa

Table 29.2 Staining patterns of commonly used markers in usual colorectal adenocarcinoma

Fig. 29.1

An example of metastatic colonic adenocarcinoma involving small intestinal mucosa. SATB2 nuclear immunoreactivity highlights metastatic tumor cells in the right while the normal small intestinal glands lack immunoreactivity

Table 29.3 Markers helpful in differentiating common benign glandular proliferative lesions involving the appendix

Table 29.4 Useful markers differentiate goblet cell adenocarcinoma, classic neuroendocrine tumor, and conventional adenocarcinoma

Fig. 29.2

Goblet cell carcinoid tumor of the appendix. H&E tissue section shows the tumor cells with goblet cell morphology infiltrating the appendiceal wall (a). The tumor cells demonstrate positive nuclear immunoreactivity for CDX2 (b), CK20 (c) and CK7 (d). The tumor cells are also positive for synaptophysin and chromogranin (not shown)

Table 29.5 Markers to distinguish mucinous tumors of appendiceal versus ovarian origin

Table 29.6 Commonly used markers for diagnosis of Hirschsprung’s disease and potential pitfalls

Fig. 29.3

Loss of calretinin immunoreactivity in hypertrophied nerve bundles in Hirschsprung’s disease. Nerves and ganglia show positive immunoreactivity for calretinin in normal control (a). In addition to the absence of ganglion cells, the thick nerve bundles in Hirschsprung’s disease exhibit loss of calretinin immunoreactivity (b)

Table 29.7 Different staining patterns between usual colonic adenocarcinoma and some of its unique variants

Fig. 29.4

Colonic medullary carcinoma. Hematoxylin and eosin (H&E) tissue section shows a sheet of tumors with primitive appearance (a); tumor cells show membranous immunoreactivity to CDH17 (b) and nuclear immunoreactivity to SATB2 (c). In addition, they are also strongly and diffusely positive for calretinin (d)

Table 29.8 Markers to differentiate colorectal adenocarcinoma from metastatic adenocarcinomas of the breast , pancreas, and lung

Table 29.9 Markers to differentiate colorectal adenocarcinoma from common gynecological carcinomas

Table 29.10 Markers to differentiate colorectal adenocarcinoma from primary adenocarcinomas of the bladder, urachus, and prostate

Table 29.11 Markers to differentiate colorectal adenocarcinoma from peritoneal mesothelioma

Table 29.12 Markers to distinguish well-differentiated neuroendocrine tumors (WD-NETs) of the colorectal origin versus other organ systems

Table 29.13 Markers to differentiate common colonic mucosal mesenchymal polyps

Fig. 29.5

Schwann cell hamartoma and intestinal mucosal perineureoma. Hematoxylin and eosin (H&E)-stained sections of both lesions show spindle cell proliferation without ganglion cells. Schwann cell hamartoma, H&E stain (a) and demonstrating diffuse and strong immunoreactivity to S100 (b); intestinal mucosal perineurioma, H&E stain (c), and demonstrating positive immunoreactivity to GLUT 1 (d)

Table 29.14 Markers to differentiate common mesenchymal tumors of the colon and rectum

Fig. 29.6

Granular cell tumor of the ascending colon. The tumor cells exhibit characteristic eosinophilic granular cytoplasm (a). They are strongly and diffusely positive for S100 (b)

Table 29.15 Markers useful to confirm dysplasia in inflammatory bowel disease (IBD) and to differentiate IBD-associated dysplasia from sporadic adenoma

Table 29.16 Common mismatch repair (MMR) protein nuclear expression patterns and risk assessment of Lynch syndrome

Fig. 29.7

Algorithm to assess the risk of Lynch syndrome in colorectal carcinoma

Table 29.17 Markers to differentiate adenocarcinoma of anal duct origin from small intestinal, colorectal adenocarcinoma , endocervical and prostatic adenocarcinoma

Fig. 29.8

Anal gland adenocarcinoma. The tumor cells exhibit positive CK7 immunoreactivity

Table 29.18 Markers to distinguish anal Paget’s disease versus melanoma in situ

Fig. 29.9

Anal Paget’s disease with underlying mucinous adenocarcinoma. The tumor cells involve the overlying epidermis with pagetoid spreading and exhibit positive CK 20 immunoreactivity

Table 29.19 Markers for anal squamous cell carcinoma versus basal cell carcinoma versus melanoma versus urothelial carcinoma versus small cell carcinoma

Note for All Tables:

“+”—usually greater than 70% of cases are positive; “−”—less than 5% of cases are positive; “+ or −”—usually more than 50% of cases are positive; “− or +”—less than 50% of cases are positive: ND—no data available; V—variable.