Posted July 26, 2011

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

A mass in the ileum was noticed during surgery in a 60-year-old man undergoing appendectomy. Segmental bowel resection was performed which showed a 5.6 cm intramural mass. Sectioning revealed a circumscribed tumor without hemorrhage or necrosis. Immunohistochemistry showed that the tumor cells were Kit (CD117) (+), smooth muscle actin (+) and S100 (-).

Archive Case and Diagnosis: This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2008, Case 23, and is gastrointestinal stromal tumor.

Criteria for Diagnosis and Comments: The sections show a spindle cell neoplasm with cells arranged in short, haphazard fascicles. The tumor cells contain relatively bland, uniform, elongated nuclei with vesicular chromatin and inconspicuous nucleoli. Mitotic figures are rare to absent. Prominent vessels in a staghorn-like pattern are seen focally. The morphology and immunophenotype (see Clinical Summary) establish the diagnosis of gastrointestinal stromal tumor (GIST).

GISTs are most common in the stomach (60%), but can occur throughout the gastrointestinal tract (jejunum and ileum 30%, duodenum 5%, colon and rectum <5%, esophagus <1%). The majority of these tumors are sporadic with only less than 5% of the cases associated with certain familial syndromes including neurofibromatosis type 1, Carney triad, and familial GIST syndrome. Malignant behavior is observed in 20-25% of gastric and 40-50% of small intestinal GISTs. Abdominal cavity and liver are the most common sites of metastasis, while spread to other sites is rare. Metastasis can develop more than 10 years after surgery.

Histologically, GISTs may display a spindle cell, epithelioid, mixed or rarely pleomorphic morphology. Compared to the stomach, epithelioid GISTs are uncommon in the small intestine and are usually associated with an aggressive outcome. GISTs are not designated as benign or malignant, but the risk for aggressive behavior is stratified based on two parameters: tumor size and mitotic activity. Recent studies have revealed that small intestinal GISTs are more likely to be malignant compared to gastric GISTs of similar size and mitotic activity (Table 1). The present case is classified as moderate risk (size>5 cm and mitoses<5/50 high power fields).

The defining molecular characteristic of GISTs is the presence of mutations in the KIT gene, which are present in 85-90% of cases. A subset of GISTs lacking KIT mutations shows mutations in PGFRA (platelet derived growth factor receptor-alpha) gene. Around 5-10%of GISTs are negative for both KIT and PDGFRA mutations. GISTs with PDGFRA often have epithelioid morphology and generally occur in the stomach. GISTs in the pediatric population are rare (<1%) but are not caused by KIT or PDGFRA mutations suggesting a different molecular mechanism. Imatinib mesylate (Gleevec), a tyrosine kinase inhibitor, is effective against most GISTs with KIT and PDGFRA mutations. The exact site of KIT or PDGFRA mutation can predict response to imatinib. For example, GISTs with exon 11 KIT mutations show an excellent response to therapy, mutations in exon 13 or exon 17 are relatively resistant and mutations in exon 9 respond to a higher dose of imatinib. Hence determining the type of mutation may become a routine practice in the future while considering therapy. Despite initial response to imatinib, subsequent disease progression often occurs due to secondary mutations.

* These criteria are different from the consensus recommendations published in 2002 and are based on the recent large series by Miettinen et al.

Immunohistochemical expression of KIT is seen in >95% of GISTs. In most cases, the staining is strong, diffuse and cytoplasmic. Dot-like (Golgi pattern) and membranous patterns can also occur. The majority of KIT-negative GISTs have mutations in the PDGFRA gene, but can have KIT mutations as well. Hence absence of KIT on immunohistochemistry should not be used to exclude patients from imatinib treatment. KIT expression is not specific for GIST, and has also been observed in melanoma, mastocytosis, seminoma, pulmonary small cell carcinoma, angiosarcoma and granulocytic sarcoma. Normal mast cells, which express KIT, may be found in various tumors and can give a false positive result. Weak KIT reactivity has also been reported in mesenteric fibromatosis although this observation is dependent on the specific commercial antibody being used, with higher antibody dilutions showing negative results.

The expression of DOG1 gene was identified in GISTs by gene expression studies. Immunohistochemical expression of DOG1 has high sensitivity (97-100%) for GIST and is positive in most or all KIT-negative GISTs. Weak DOG1 expression has been observed in a small minority of mesenteric fibromatosis and smooth muscle tumors. Protein kinase C theta and nestin also have high sensitivity, but have limited diagnostic utility due to lower specificity. Other markers seen in GISTs include CD34 (60-70%), smooth muscle actin (30-40%), caldesmon (80%) and S100 (5-10%, focal).

Gastrointestinal leiomyomas most often occur in the esophagus and rectosigmoid colon. Extramural masses in the colon resembling uterine leiomyoma can also occur. In contrast with GISTs, smooth muscle tumors show brightly eosinophilic cytoplasm, elongated blunt-ended nuclei and better defined cell borders. These lesions are easily distinguished from GIST based on negative KIT staining and diffuse expression of desmin. Although caldesmon and smooth muscle actin are often expressed in GIST, desmin positivity (focal) is seen in <2% of GISTs.

Schwannomas of the gastrointestinal tract usually occur in the stomach or colon and are rarely found in the esophagus or small intestine. The presence of a prominent lymphoid infiltrate at the periphery of the tumor and prominent hyalinized blood vessels are helpful histologic clues. These tumors are S100 positive and negative for KIT.

Mesenteric fibromatosis appears as a hard white mass and histologically shows infiltrative borders, fat entrapment, interstitial collagen and prominent often evenly spaced blood vessels. The majority of fibromatoses (90% in one series) show aberrant nuclear expression of β-catenin by immunohistochemistry. This finding is not seen in GISTs. Focal expression of smooth muscle actin and desmin can occur in fibromatosis, but S100 is negative.