Francisco G. La Rosa MD Pathologist, Assistant Professor Department of Pathology, UCHSC * In collaboration with * In collaboration with S. Russell Nash, MD, PhD UCDHSC at Fitzsimons Mail Stop 8104, P.O. Box 6511 Phone: Fax: – This presentation is copyrighted and cannot be reproduced in whole or in part without the authors’ permission Pathology Review Gastrointestinal Stromal Tumors* December 16, Denver – Colorado Pathology Review Gastrointestinal Stromal Tumors* December 16, Denver – Colorado

Normal Histology of the GI tract Muscularis propria Serosa Mucosa Submucosa

Gastrointestinal Stromal Tumors (GIST) are a rare but important group of spindle cell tumors arising within the gastrointestinal tract. For many years, these tumors were misdiagnosed as leiomyomas, epithelioid leiomyomas, leiomyoblastomas, leiomyosarcomas, and epithelioid leiomyoblastomas, depending upon the histologic findings. The cell of origin has been found to be a mesenchymal stem cell, and not the smooth muscle cell as once thought. GISTs arise from the Interstitial Cajal Cells, that are normally part of the autonomic nervous system of the intestine. They serve a pacemaker function in controlling motility. Most of these tumors present with pain, obstruction, a mass lesion, or bleeding. Most (50-80%) GISTs arise because of a mutation in a gene called c-kit. This gene encodes a transmembrane receptor for a growth factor termed scf (stem cell factor). The c-kit/CD117 receptor is expressed on ICCs and a large number of other cells, mainly bone marrow cells, mast cells, melanocytes and several others. In the gut, however, a mass staining positive for CD117 is likely to be a GIST, arising from ICC cells. The pathologist is faced with the task of identifying prognostic factors that may provide guidance for treatment and survival.

Differential Diagnosis Gastrointestinal Spindle Cell Tumors Leiomyoma/LeiomyosarcomaLeiomyoma/Leiomyosarcoma Schwannoma/Malignant peripheral nerve sheath tumorSchwannoma/Malignant peripheral nerve sheath tumor Solitary fibrous tumorSolitary fibrous tumor Fibromatosis (desmoid tumor)Fibromatosis (desmoid tumor) Inflammatory myofibroblastic tumorInflammatory myofibroblastic tumor Inflammatory fibroid polyp (in stomach)Inflammatory fibroid polyp (in stomach) GISTsGISTs

GIST Sites Stomach50-60% Small bowel 20-30% Large bowel 10% Esophagus5% Mesentery, omentum, retroperitoneum Rare

Gastric GIST - Tumoral nodules under the gastric mucosa

Gastric GIST

Stomach resection of 72 year old man with gastric leiomyosarcoma. Note that normal mucosa is present at the right side of the photograph. The tumor invades full-thickness and completely obliterates the gastric wall.

GIST tumor arising in small bowel. Note the mass lies underneath and is separate from the bowel mucosal layer and there is no disruption of the overlying mucosa. The deep location of the tumor makes it difficult to obtain endoscopic biopsies in many cases.

Colonic GIST

Benign spindle cell GIST

Benign epithelioid GIST with multinucleated cells

Benign spindle cell GIST with extensive perinuclear vacuolization (typical feature)

Risk of Aggressive Behavior in GI Stromal Tumors RiskSizeMitoses (per 50 hpf) Very low < 2 cm < 5 Low 2-5 cm <5 Intermediate< <5 High>5>5 >10 Any number Any size >10 From: Fletcher, CDM et al Hum. Pathol. 33:

Histologic Features Suggesting Malignant Behavior in GIST Cell type: Epithelioid>Spindle CellCell type: Epithelioid>Spindle Cell CellularityCellularity Mitotic activityMitotic activity Mucosal invasionMucosal invasion Tumor necrosisTumor necrosis From: Goldblum, JR 2002 Am. J. Clin. Pathol. 117Suppl: S49-S61

High cellularity and many mitoses suggest an aggressive behavior for this tumor.

Immunophenotypes of Spindle Cell Tumors LesionCD117CD34DesminActinS100 GIST++/---/+- Leiomyoma--++- Fibromatosis---/++- Solitary fibrous T Schwannoma--/+--+ (pos = >75%) ( +/- = 50-75%) (-/+ = 25-50%) (neg = 75%) ( +/- = 50-75%) (-/+ = 25-50%) (neg = <25%) Actin = smooth muscle type CD117 = sc-168 Santa Cruz Biotechnology

CD117 staining in spindle cell GIST

Gastric leiomyoma with smooth muscle type spindle cells arranged in fascicles and bundles. There is no perinuclear vacuolization.

Intra abdominal fibromatosis (desmoid like) showing low cellularity and collagenous stroma.

Leiomyosarcoma – low power view shows increased cellularity and cytological atypia.

High power view of leiomyosarcoma with marked cytological atypia.