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14 June 2017 - Case of the Week #428

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Case of the Week #428

Clinical history:
A 71 year old man underwent transanal endoscopic microsurgery for a large rectal tubuvillous adenoma. An incidental microscopic finding was noted in the specimen.

Microscopic images:

Various images

What is your diagnosis?

Interstitial cell of Cajal hyperplasia (localized type)

Special stains:


Test question (answer at the end):

True or False:
The majority of interstitial cell of Cajal hyperplasia lesions are obligate precursors of gastrointestinal stromal tumors (GISTs) and demonstrate heterozygous somatic mutations of cKIT.


Interstitial cells of Cajal (ICC) function as "pacemakers" of the GI tract, initiating and maintaining peristalsis. They strongly express cKIT and DOG1 and variably express CD34. Hyperplasia of the interstitial cells of Cajal is the microscopic proliferation of these cells in the myenteric plexus of the gastrointestinal tract, regardless of the associated clinical milieu.

Microscopic images show focal proliferation of bland spindle cells with an irregular border located in the muscularis propria and extending into the pericolorectal soft tissue.

ICC hyperplasia may be focal or diffuse and occur in the setting of genetic syndromes or as a sporadic (incidental) finding. Sporadic or incidentally found foci of hyperplasia have an indolent course, and likely involute spontaneously. ICC hyperplasia seen in genetic syndromes (including germline mutations of cKIT, PDGFRA or NF1 or Carney’s triad with succinate dehydrogenase mutations) predispose to multiple gastrointestinal stromal tumors (GISTs) (Int J Clin Exp Pathol 2013;6:2989, Int J Surg Case Rep 2015;16:202). Most sporadic ICC hyperplasia lesions are seen in the distal esophagus, stomach or small intestine, with only rare lesions described in the colorectum (0.2% of routine specimens).

The nomenclature of incidental small proliferations of interstitial cells of Cajal is controversial. A four tier classification system has been suggested: ICC hyperplasia-localized type (≤5 mm, solitary), ICC hyperplasia-diffuse type (variable size, multiple or diffuse, may be confluent), GIST tumorlets (5-10 mm), and incidental, benign GISTs (>10-20 mm) (Int J Clin Exp Pathol 2010;3:549). Some authors prefer the term "microscopic GISTs", arguing the tendency of these lesions to infiltrate the surrounding muscularis propria suggests a neoplastic as opposed to hyperplastic nature. Others render a diagnosis of "benign GIST" only in asymptomatic, very small lesions (< 10 mm) incidentally found during abdominal surgery for other reasons, arguing that any GIST has the potential for metastasis. Tumor size and mitotic rate are the most important prognostic factors in GIST (Int J Surg Pathol 2002;10:81).

The differential diagnosis of these lesions from a morphologic perspective may include small foci of fibromatosis, inflammatory myofibroblastic tumor, leiomyoma and leiomyosarcoma. These four lesions do not typically express DOG1, and only rarely express cKIT (fibromatosis).

Localized hyperplasia of the interstitial cell of Cajal, as in this case, is usually a focal and incidental finding on microscopic examination, has an indolent course and demonstrates heterozygous somatic mutations in cKIT less commonly (~25%) than large or symptomatic GISTs (75 – 90%).

Additional references:

1. Rossi, S. et. al. Molecular and Clinicopathologic Characterization of Gastrointestinal Stromal Tumors (GISTs) of Small Size. (Am J Surg Pathol 2010;34:1480)

2. Streutker, C. J et. al. Interstitial cells of Cajal in health and disease. Part I: Normal ICC structure and function with associated motility disorders. (Histopathology 2007;50:176)

3. Streutker, C. J et. al. Interstitial cells of Cajal in health and disease. Part II: Normal ICC structure and function with associated motility disorders. (Histopathology 2007;50:190)

4. Agaimy A et. al. Microscopic gastrointestinal stromal tumors in esophageal and intestinal surgical resection specimens. A clinicopathologic, immunohistochemical, and molecular study of 19 lesions. (Am J Surg Pathol 2008;32:867)

5. Fletcher, CD, Berman, JJ, Corless, C, et al. Diagnosis of gastrointestinal stromal tumors: A consensus approach. (Int J Surg Pathol 2002;10:81)

Test Question - Answer:

Localized hyperplasia of the interstitial cell of Cajal, such as the case discussed here, is usually a focal finding incidentally noted on microscopic examination, has an indolent course and demonstrates heterozygous somatic mutations in cKIT less commonly (~25%) than large GISTs (75 – 90%).

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