School of Medicine

Department of Pathology

Answer and Discussion

The H&E sections show a polypoid lesion composed predominantly of conventional adenoma. No high-grade dysplasia is noted. At high power, there are small nests that are sparsely dispersed at the base of the polyp and are infiltrative into the superficial muscularis mucosa. Though the pattern is concerning, the cells have bland cytology, with scant eosinophilic cytoplasm and round central nuclei. They are devoid of nuclear atypia, hyperchromasia, or nuclear pleomorphism. By immunohistochemistry, these cells are positive for synaptophysin and beta-catenin (nuclear staining). Ki67 shows a very low proliferative rate. Given these morphologic features and immunophenotype, this is a composite intestinal adenoma-microcarcinoid (CIAM).

CIAM is a rare intestinal lesion consisting of a conventional adenoma and small, well differentiated microcarcinoids at its base. This entity was initially reported by Moyana and Murphy in 19884, and its rarity contributes to diagnostic challenges in making an accurate diagnosis. Recently, an incidence of 3.8% was reported from one tertiary care center cohort of 158 surgically resected colorectal polyps.

 CIAM is clinically identified in middle-aged to elderly patients, with a reported mean age of 60 years. These are predominantly found in the colon, usually in the cecum and right colon, and present as polyps with well-defined margins, similar to conventional adenomatous polyps. Most reported CIAMs are sporadic and found incidentally. While colorectal microcarcinoids have been described in patients with chronic colitis including diversion colitis and inflammatory bowel disease, especially ulcerative colitis, however, the incidence of CIAM in patients with inflammatory conditions is unknown.

The pathogenesis of CIAM is not well understood. The findings of CIAM in familial adenomatosis polyposis patients support the role of Wnt/β-catenin pathway in the tumorigenesis of CIAM.

CIAMs tend to be associated with high-risk adenomas (high-risk features in adenoma include size ≥ 10 mm, villous components and/or high-grade dysplasia). CIAMs do not form grossly evident nodules or masses. Histologically, these are composed predominantly of conventional adenomas with the microcarcinoid (MC) component usually situated in the basal portion of the lamina propria. Superficial invasion of the submucosa by the MC component has been reported. The MC components are often connected to the overlying glandular components and sometimes it is difficult to distinguish one from the other. The MC cells are usually arranged in clusters, nests, tubules, cords, or can be dispersed singly. The surrounding lamina propria may have features mimicking desmoplasia with pale and slightly edematous stromal cells admixed with inflammatory cells, including occasional prominent eosinophilia. The MC nests often arrange in a lobular architecture. Cytologically, the MC cells are usually bland, small and uniform with a moderate amount of eosinophilic, granular, or pale cytoplasm. The nuclei are relatively uniform, round and centrally located with finely stippled chromatin and inconspicuous nucleoli. Mitotic figures or necrosis are not observed.

By immunohistochemistry, the MC components are positive for synaptophysin, supporting their neuroendocrine differentiation. Chromogranin-A and CD56 can have variable positive staining. The MC component shows nuclear β-catenin positivity in 60-100% of the cases, suggesting the role of Wnt/β-catenin pathway in the CIAM tumorigenesis. The MC components are usually well-differentiated with a low Ki-67 proliferation index (usually < 1-2%), although sometimes the total number of neuroendocrine cells may be insufficient (< 500 cells in total) for a reliable Ki-67 index measurement.

CIAMs have an indolent disease course and a favorable outcome. Complete removal of both adenoma and MC by polypectomy is considered curative. Additional radical surgeries are reserved for cases with adverse histologic features such as deep submucosal extension or increased proliferative activity of the MC component.

MC can resemble squamous morules/metaplasia, invasive adenocarcinoma, squamous cell carcinoma (SCC), sporadic neuroendocrine tumor, and goblet cell adenocarcinoma (GCA), hence MC in CIAMs may pose a diagnostic challenge. A high index of suspicion for this entity will avoid a misdiagnosis or an overdiagnosis of a malignancy.

Squamous morules/metaplasia is an incidental histologic lesion that can be seen in colorectal adenomas. There can be significant histomorphologic overlap between the MC component of CIAM and squamous morules. Both can present as solid nests around the bottom of adenomatous glands or in a myxoinflammatory stroma. However, the squamous morules tend to be randomly distributed in the adenoma with a more strong and diffuse staining for CK5/6. SCC is considered in the differential of the MC component of CIAM since these can resemble squamous morules as mentioned above. Primary colorectal SCC is a rare malignancy which presents late in the disease course and shows an aggressive behavior with early metastasis.

MC components of CIAM may be misdiagnosed as invasive adenocarcinoma or tumor budding. A bland cytoarchitecture and negligible mitotic activity of MC, along with awareness of CIAM are helpful to avoid a misdiagnosis. Confirming neuroendocrine differentiation can be a useful diagnostic tool in challenging cases.

Treatments for CIAMs and sporadic neuroendocrine tumors are different, therefore it is important to distinguish the two. The MC components in CIAMs are usually situated at the polyp base in the mucosa, whereas the usual epicenter of sporadic neuroendocrine tumors is the submucosa. β-catenin expression may play a role in making the diagnosis since some studies have observed a significantly higher β-catenin expression score in CIAMs.

GCA is an amphicrine tumor containing goblet-like mucinous cells admixed with endocrine and Paneth-like cells, usually arranged singly or as tubules resembling intestinal crypts. The tumor nests are variably positive for neuroendocrine markers and mucin. GCA may co-exist with adjacent cecal adenomas, which may erroneously be interpreted as a CIAM. Clinically, GCA is an aggressive tumor and often presents with metastatic disease whereas CIAMs usually have a benign course.

Lastly, CIAM is distinct from mixed neuroendocrine-non-neuroendocrine neoplasm (MiNEN). MiNEN is an umbrella term referring to a neoplasm with both neuroendocrine and non-neuroendocrine components, often with a high grade/malignant component, such as neuroendocrine carcinoma or adenocarcinoma. It is required that each component constitutes a minimum 30% of the neoplasm to qualify for MiNEN.

In conclusion, CIAM is a rare intestinal lesion consisting of a conventional adenoma and a well differentiated MC component at its base. MC in CIAM poses diagnostic challenges with its morphologic resemblance to other benign and malignant lesions. Raising awareness of this rare entity is important to avoid misdiagnosis.  

 

References

  1. Fu ZY, Kmeid M, Aldyab M, Lagana SM, Lee H. Composite intestinal adenoma-microcarcinoid: An update and literature review. World J Gastrointest Endosc. 2021 Dec 16;13(12):593-606.
  2. Fu Z, Saade R, Koo BH, Jennings TA, Lee H. Incidence of composite intestinal adenoma-microcarcinoid in 158 surgically resected polyps and its association with squamous morule.Ann Diagn Pathol. 2019;42:69–74.
  3. Lin J, Goldblum JR, Bennett AE, Bronner MP, Liu X. Composite intestinal adenoma-microcarcinoid. Am J Surg Pathol. 2012;36:292–295.
  4. Moyana TN, Qizilbash AH, Murphy F. Composite glandular-carcinoid tumors of the colon and rectum. Report of two cases.Am J Surg Pathol. 1988;12:607–611.
  5. Fahim F, Al-Salamah SM, Alam MK, Al-Akeely MH. Squamous cell carcinoma of colon and rectum. Saudi Med J. 2006;27:874–877. 
  6. Estrella JS, Taggart MW, Rashid A, Abraham SC. Low-grade neuroendocrine tumors arising in intestinal adenomas: evidence for alterations in the adenomatous polyposis coli/β-catenin pathway.Hum Pathol. 2014;45:2051–2058.
  7. La Rosa S, Uccella S, Molinari F, Savio A, Mete O, Vanoli A, Maragliano R, Frattini M, Mazzucchelli L, Sessa F, Bongiovanni M. Mixed Adenoma Well-differentiated Neuroendocrine Tumor (MANET) of the Digestive System: An Indolent Subtype of Mixed Neuroendocrine-NonNeuroendocrine Neoplasm (MiNEN) Am J Surg Pathol. 2018;42:1503–1512.
  8. Salaria SN, Abu Alfa AK, Alsaigh NY, Montgomery E, Arnold CA. Composite intestinal adenoma-microcarcinoid clues to diagnosing an under-recognised mimic of invasive adenocarcinoma.J Clin Pathol. 2013;66:302–306.
  9. WHO Classification of Digestive System Tumors (5th Edition), Online Version. International Agency for Research on Cancer. Available from: https://tumourclassification.iarc.who.int/chaptercontent/31/52

 

Board type review questions

  1. The following statements are all true regarding composite intestinal adenoma-microcarcinoid except: 
    1. It does not form gross nodule or mass.
    2. It has a tendency to be associated with high-risk adenoma.
    3. Microcarcinoid components are usually dispersed in the lamina propria and have a bland cytology and low proliferative index.
    4. It shows aggressive behavior with early metastasis.
  2. By immunohistochemical staining, the microcarcinoid components in CIAM show positivity for all of the following except:
    1. Synaptophysin, chromogranin-A and CD56
    2. p63 and CK5/6
    3. Mutational type P53 expression
    4. Nuclear β-catenin

      D.

      C.