Pathologists share their data on GIST

Armed Forces Institute of Pathology researchers have focused on GIST

First of two parts

By Markku Miettinen, M.D., and Jerzy Lasota

The opinions and assertions in this article are the views of the authors and are not to be construed as reflecting the views of the Departments of the Army or Defense. The authors work for the American Registry of Pathology, contracted to work in the Armed Forces Institute of Pathology, offering consultation to government and civilian institutions worldwide. The authors wish to acknowledge the support of Department Defense and American Registry of Pathology in writing this article, as well as the encouragement of the Life Raft Group and its executive director, Norman Scherzer.

TERMINOLOGY and BACKGROUND

Until a few years ago, the non-epithelial (mesenchymal) tumors of the gastrointestinal tract were commonly classified as smooth muscle tumors under headings of leiomyoma (an expectedly benign tumor) and leiomyosarcoma (an expectedly malignant tumor). In recent years it has been increasingly apparent that these tumors were unique, different from leiomyomas and leiomyosarcomas of the peripheral soft tissues — although a very small group of true leiomyomas and leiomyosarcomas does exist in the gastrointestinal tract. In the past six years, the understanding of these tumors has significantly advanced, including the pathologic mechanism and new treatments based on it.

Gastrointestinal stromal tumor (GIST) is now defined as a specific group of immunohisto-chemically KIT-positive mesenchymal tumors of the gastrointestinal (GI) tract driven by KIT cell signaling. Alternative KITlike receptor, PDGFRA seems to be involved in a number of cases. The specific identification of GIST and recognition of pathogenesis has gained a whole new meaning after the availability of Gleevec/Glivec, a KIT- and PDGFRA-selective tyrosine kinase inhibitor, for treating unresectable and metastatic GISTs. However, it should be stressed that a majority of these tumors are nonmalignant and benign, especially those tumors that originate from the stomach. Therefore, a majority of patients with these tumors do not require further treatment following surgery. However, clinical follow-up is generally recommended.

OCCURRENCE and ETIOLOGY (CAUSE)

GISTs are the most common mesenchymal (nonepithelial) tumors of the GI tract, and encompass most tumors previously classified as gastric and intestinal smooth muscle tumors. However, they are much less common than epithelial tumors, adenomas and carcinomas of the GI tract, comprising less than 1 percent of all GI tumors. GISTs typically show up in adults over 40 years (median age 55-60 years). Approximately 10 to 20 percent of these tumors occur in people under 40, but only 1 percent or less in children — practically never before the age of 10. These tumors often occur in old age, and are sometimes diagnosed at age 90 or beyond.

GISTs are equally common in men and women. The cause of GISTs is unknown, as is for most other mesenchymal tumors.

Rarely, GIST occurs as a part of a tumor syndrome. These syndromes are familial GISTs (extremely rare), Carney’s triad (GIST, paraganglioma and pulmonary chondroma), and neurofibromatosis 1 (NF1); the latter is the most common GIST syndrome. The NF1 patients with GISTs typically have multiple small intestinal tumors, and severe bleeding can be a lifethreatening complication. Patients with familial GISTs have inheritable KIT mutations, but molecular pathogenesis of GIST in the two latter syndromes is unknown. Only a very small portion of GISTs (< 5 percent) are associated with any of these syndromes.

CLINICAL PRESENTATION

GIST can present anywhere in the GI tract, from the lower esophagus to the anus. A majority of them occur in the stomach (60-70 percent) and small intestine (25-35 percent). Colon, rectum, appendix (together 5 percent) and esophagus (2-3 percent) are rare sites. Some GISTs are primary in the omentum, mesentery or retroperitoneum, unrelated to the tubular GI tract, but most GISTs in these sites are metastases from gastric or intestinal primary. Estimates of frequency of malignancy vary; our estimate for gastric GISTs is 20-30 percent, and 30-50 percent for intestinal ones. Malignant GISTs most commonly metastasize to the abdominal cavity and the liver, and rarely in bones, soft tissue and lungs.

The clinical presentation of GIST varies. Up to 30 percent of these tumors are detected as asymptomatic masses and nodules during the diagnosis and treatment of other abdominal conditions. Especially, many of these tumors in the stomach are detected as very small lesions during abdominal surgery for other benign and malignant diseases. Common background situations include gall bladder surgery, endoscopic screening for cancer or other pathology, or operation for carcinomas of stomach, colon and kidney. In some cases, the patients or doctors note asymptomatic tumors; a moderate size tumor can sometimes be felt through the skin of a skinny person.

Approximately 70 percent of GISTs are symptomatic. Most commonly they cause gastrointestinal bleeding originating from an ulcerated tumor. This can be gradual and insidious internal bleeding often leading to marked anemia and weakness before the tumor is ultimately detected. In some patients, the bleeding is acute, presenting as black stools (melena), or less commonly as hematemesis (throwing up blood). Some patients have vague symptoms caused by a tumor mass or an ulcerated tumor; in the latter case the symptoms can be similar to gastric ulcer, or in case of malignant GISTs, similar to those of gastric cancer. Intestinal GISTs occasionally cause obstruction. In rare cases, the tumor ruptures inside the abdomen and causes intra-abdominal hemorrhage with acute symptoms. In some cases, large tumors originating from the stomach are clinically thought to originate from the liver or pancreas because of their proximity to these organs.

SUMMARY OF TISSUE PATHOLOGY and DIAGNOSIS

GISTs vary widely in their size and shape, and to some degree, in their microscopic appearances.

They vary from very small (almost always benign) tumors to very large (and often malignant) tumors. Small gastric and intestinal GISTs are often found as a small nodule on the external surfaces of these organs. Many tumors involve the entire wall, and some extend internally as polyps, and others externally sometimes being attached only by a narrow pedicle. Ulceration is common in GISTs of all sites, and is not related to tumor malignancy. Calcification is relatively rare and is usually seen in small tumors. The larger tumors are often microscopically or grossly cystic, and the contents of larger cysts vary from clear fluid to darkbrown material.

The microscopic (histologic) features of GIST vary, and to some degree this variation is site-dependent, the gastric and intestinal tumors being somewhat different. Most commonly, GISTs have a spindle cell pattern composed of elongated, tapered cells (60-70 percent), whereas epithelioid cytology with polygonal cells is seen in 20-30 percent of cases exclusively or focally, and pleomorphic (atypical, anaplastic) pattern rarely (< 5 percent).

SPECIFIC DIAGNOSIS of GIST

The diagnostic specimen can be a needle biopsy, endoscopic biopsy, open biopsy or resection specimen. Needle biopsy is sometimes obtained before surgery of primary tumor, and it is the usual specimen type obtained from metastasis. Endoscopic biopsy is often successful in diagnosing an ulcerated GIST, but tumors that haven’t ulcerated are usually inaccessible by endoscopic biopsy. Open biopsy during laparoscopy or laparotomy is sometimes obtained from larger tumors, and it may be submitted for rapid (frozen section) diagnosis during surgery. Resection specimen is the one originating from the definitive surgery. This can be a small or large resection of stomach or intestines, depending on the location and extent of the tumor, as required for complete tumor removal.

The histologic features of GIST include spindle cell or epithelioid morphology. Mitotic activity is the key parameter to determine biologic potential, and is typically expressed as mitoses per 50 high power fields. GISTs are typically immunohistochemically KIT-positive, as determined from tumor tissue sections via a somewhat complex sequence of a laboratory procedure. This is a major diagnostic feature of GIST and has generally been a requirement for entering into clinical trials. This may change, if mutation status and alternative PDGFRA involvement are being considered. In summary, the diagnosis is based on the combination of histologic, immunohistochemical, and possibly analysis of KIT and PDGFRA mutations.

The second part of this article will be published in the next newsletter.

About the authors: Pathologist Markku Miettinen, 51, is the chairman and distinguished scientist of the Department of Soft Tissue Pathology of the AFIP where he’s worked since 1996. His current research focus is GIST pathology. He worked eight years as a pathologist in Thomas Jefferson University Hospital in Philadelphia, Penn., and 10 years at the University of Helsinki, Finland, his native country. Jerzy Lasota, 47, has been a pathologist at the Department of Soft Tissue Pathology since 1996. He currently specializes in molecular pathology of GIST, and is responsible for the department’s laboratory. He did seven years of cancer research in Kimmel Cancer Center/Department of Pathology and the Fels Research Institute in Thomas Jefferson and Temple Universities in Philadelphia, and seven years in the Medical Academy of Lodz, Poland, his native country. Together the authors have published more than 30 scientific articles on gastrointestinal stromal tumors.

Address for correspondence: Markku Miettinen, M.D. Department of Soft Tissue Pathology Armed Forces Institute of Pathology 14th Street and Alaska Avenue, N.W. Washington, DC 20306-6000, USA Phone: (202) 782-1575 E-mail: miettinen@afip.osd.mil