Microscopic description:

The small bowel resections shows two prominent tumor foci measuring 3 cm and 1 cm in greatest dimension and 0.4 cm apart (Gross image). In addition, multiple nodules measuring < 5 mm were noted on the serosal surface.

Microscopically the tumors were in submucosa and replacing the muscularis propria (HE-1) and comprised of spindle cells arranged in fascicles and bundles (HE-3). The individual cells had bland morphology without any atypia or increased mitoses (2 mitoses per 5mm2 ).

There were multiple areas of Cajal cell hyperplasia in the myenteric plexus of the muscularis propria of the jejunum and duodenum(HE-2).

On IHC, tumor showed diffuse expression for CKIT (CD117) and DOG-1 supporting the diagnosis of Gastrointestinal stromal tumor (GIST). SDHB immunostain showed intact expression in the tumor. Also, the small serosal nodules are histologically consistent with minute GISTs (GIST tumorlets).

Mesenteric fat demonstrated two lesions comprised of benign spindled cells (submitted grossly as lymph nodes, HE-4&5). S100 highlighted the Schwann cells and CD34 highlighted the stromal cells. CKIT is negative. The histologic findings in these two lesions were consistent with neurofibromas.

Discussion:

GISTs are common mesenchymal tumor of the gastrointestinal tract (usually benign/can be malignant).

Cell of origin: Intestinal cell of Cajal.

They may show differentiation towards smooth muscle cells, neural cells, mixed (both), or neither cell types.

Extra gastrointestinal GIST: omentum, mesentery, retroperitoneum or pleura.

Most common site: stomach.

3 histologic types: spindle, epithelioid and mixed.

Prognosis: depends on tumor size, mitotic rate and site of origin.

Treatment: surgical excision or imatinib.

Genes involved :mutations in c-Kit gene and PDGFRA. Proto oncogenes which causes constitutive activation of tyrosine kinase which leads to uncontrolled growth of Cajal cells (Rx: Imatinib which is tyrosine kinase inhibitor). KIT and PDGFRA mutations are mutually exclusive in GIST.

In some rare cases where the patient do not exhibit the typical c-Kit and PDGFRA mutation, mutation in succinate dehydrogenase (SDH) have been reported. Imatinib is usually not useful.

Rare genes involved include BRAF kinase, and protein kinase C. The majority of GISTs are sporadic in origin.


Table depicting GIST IHC findings
GIST diagnosis table
GISTs and NF1:

GISTs are commonly associated with NF1 syndrome, one of the autopsy series documented GIST in one third of the NF1 patients.

In NF1 pts GISTs occur in younger patients than sporadic GISTs and are usually multiple with common locations in the duodenum or small intestine.

Cajal cell hyperplasias in between GISTs are thought to be the precursor lesions in NF1 patients.

NF1 GISTs do generally stain positive for KIT protein (CD117), like most other GISTs.

In comparison to sporadic GISTs, NF1 GISTs are more likely to show S-100 reactivity (a marker of neural differentiation), entrapped myenteric nerves within the tumor, and skeinoid fibers within the tumor.

Peri-intestinal neurofibromas can be seen in NF1 patients.

GISTs in NF1 pts have shown to have low ki67 index and clinically indolent behavior.

GIST tumors in NF1 usually have normal or “wild type” KIT and PDGRFA genes and no loss of succinate dehydrogenase subunit B (SDHB) expression (SDH-B intact).

References:

Bulusu VR, Casey R, Giger O, Carroll N, Maher E. Neurofibromatosis 1 (NF1) and gastrointestinal stromal tumors (GISTs): Five-year experience from a regional center in United Kingdom. Journal of Clinical Oncology. 2019;37(15):11035-11035

Foo, Wai Chin et al. “Pathology of Gastrointestinal Stromal Tumors.” Clinical Medicine Insights. Pathology 5 (2012): 23 - 33.

Wu CE, Tzen CY, Wang SY, Yeh C-N. Clinical Diagnosis of Gastrointestinal Stromal Tumor (GIST): From the Molecular Genetic Point of View. Cancers. 2019; 11(5):679.

Yantiss R, Rosenberg A, Sarran L. et al. Multiple gastrointestinal stromal tumors in type I neurofibromatosis: a pathologic and molecular study. Mod Pathol . 2005;18: 475–484.

Maertens O, Prenen H, Debiec-Rychter M, et al. Molecular pathogenesis of multiple gastrointestinal stromal tumors in NF1 patients. Hum Mol Genet. 2006;15:1015–23

Miettinen M, Fetsch JF, Sobin LH, Lasota J. Gastrointestinal stromal tumors in patients with neurofibromatosis 1: a clinicopathologic and molecular genetic study of 45 cases. Am J Surg Pathol. 2006;30(1):90-6

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