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Gastrointestinal Stromal Tumors - Parameters that Determine Biologic Potential and Guide Therapy from a Surgical Pathologist's Point of View


Markku Miettinen
Armed Forces Institute of Pathology
Washington, DC


Gastrointestinal stromal tumors (GISTs) are specific KIT-positive and KIT-signaling driven mesenchymal tumors, many of which have KIT activating mutations.1-4  These tumors can occur anywhere from the distal esophagus to the anal region, and they may also present in the omentum, mesenteries and retroperitoneum,5,6  where most GISTs are metastases from gastric or intestinal primaries and only few are primary tumors. The new targeted disease mechanism-specific chemotherapy via tyrosine kinase inhibitor Imatinib (STI571/Gleevec/Glivec) seems to be effective in metastatic GIST and will probably dramatically change the natural history of the disease.7  The new treatment may make some of the traditional prognostication obsolete. However, understanding the biologic potential of GIST prior to Imatinib helps to assess the need and impact of this treatment.

GISTs present a spectrum of tumors ranging from small and benign to fully malignant sarcomas at all sites of their occurrence; therefore we do not view the site per se as prognostic factor. Clinically benign tumors clearly outnumber the malignant ones in the stomach.3,8,9  In the duodenum, approximately one third of GISTs display malignant behavior in our experience.10  In elsewhere of the small intestine and in the rectum, malignant GISTs seem equally or more common than the benign ones.11-14  We believe that the two key markers for practical prognostication are tumor size (maximum diameter) and mitotic rate (mitotic count per 50 HPF), and these criteria should be applied somewhat differently in the gastric and intestinal tumors. Because GISTs predominantly occur in older adults, the malignant potential of many tumors is not realized, as the patients often die of other causes during long-term follow-up. A significant adverse factor prior to Imatinib era is incomplete resection of gross disease.15 

The following chart is based on our experience by follow-up studies on the classification of GISTs in three groups: probably benign, probably malignant, and of uncertain (= low) malignant potential.16 

Guidelines for GIST malignancy assessment by tumor size and mitotic activity

  • Probably benign
    • Intestinal tumors
      • Maximum diameter less than 2 cm and
      • no more than 5 mitoses per 50 HPF
    • Gastric tumors
      • Maximum diameter less than 5 cm and
      • no more than 5 mitoses per 50 HPF
  • Probably malignant
    • Intestinal tumors
      • Maximum diameter over 5 cm or
      • more than 5 mitoses per 50 HPF
    • Gastric tumors
      • Maximum diameter over 10 cm or
      • more than 5 mitoses per 50 HPF
  • Uncertain or low malignant potential
    • Intestinal tumors
      • Maximum diameter 2-5 cm and
      • no more than 5 mitoses per 50 HPF
    • Gastric tumors
      • Maximum diameter 5-10 cm
      • no more than 5 mitoses per 50 HPF

Tumors that are small (< 2 cm) and lack significant mitotic activity (< 5/50 HPF) have an excellent prognosis, probably independent of site, although this has been shown only in the gastric and rectal GISTs. In the stomach, the majority of epithelioid GIST (corresponding to the former designation of epithelioid leiomyoma or leiomyoblastoma) are benign, provided that mitotic count less than 5 per 50 HPF.9  It should be noted that tumors that lack apparent mitotic activity, may metastasize. This is true especially of intestinal GISTs.

Morphologic interpretation of mitosis should be stringent when using the above chart to determine the malignant potential. The maximum tumor diameter should be taken as the size measurement. The justification of this measurement has been criticized, because some tumors are oval or oblong, and larger tumors may contain a massive cystic cavity.17  However, it is difficult to find a practical better alternative for the size measurement; this is especially true in the analysis of retrospective series.

Other histologic parameters
Coagulation necrosis seems to be strongly associated with malignancy and is a significant adverse factor in univariate analysis in some series.10  Mucosal invasion is associated with malignancy, although it is rare.12  Muscle infiltration is a key feature of GIST, especially seen in small tumors, and is not of prognostic significance. The presence of skeinoid fibers in intestinal GISTs may be a favorable sign. Ki67-index may help to identify tumors with malignant potential, but larger site-specific series are not yet available.18,19  Ulceration is common in both benign and malignant tumors and does not have significance in univariate analysis. Cellularity and organoid pattern are difficult to define and are unsuitable parameters in our experience. In one series encompassing GISTs of different sites epithelioid morphologic was an adverse sign.20  In our experience, this is the case in intestinal tumors, but we doubt that it will be in gastric tumors, where epithelioid tumors often have a benign course.9 

Immunohistochemical differentiation markers
The immunohistochemical features of GISTs vary by site. The rate of CD34-positivity (overall 70-80%) does not have prognostic significance in a large series of nearly 300 GISTs of different sites, and was not significant in a large series of duodenal GISTs.21  Neither is expression of smooth muscle actin expression (overall 20-30%) prognostically significant. The expression of keratin 18 and keratin 8 seems to be more common in malignant GISTs, but the rarity of keratin expression has so far precluded its statistical analysis in our series of rectal and duodenal GISTs.10,14 

KIT mutation and other genetic changes and malignancy
KIT mutation status and other molecular genetic markers may be useful to more accurately identify tumors with malignant potential. Currently, it is not clear whether mutations are independent prognostic markers. If indeed they are ubiquitous,22  mutation per se would not likely be significant, but mutation type could be. However, exon 9 insertion-duplication 1530 ins 6 (duplication of codons 502 Ala and 503 Tyr), originally reported by Lux et al 23 seems to be strongly associated with malignant tumors, and this mutation is nearly specific for tumors of intestinal vs. gastric origin.24  At least to some extent, in frame deletions of exon 11 involving codons 555-565 are associated with malignancy .25,26  The most notable towards Imatinib treatment are mutations in exon 17 because these are resistant. However, these mutations appear to be extremely rare in GISTs.

Other genetic changes associated with malignancy are loss of chromosome 9p and 15, and the presence of high level amplifications.27-29  LOH at 1p36 and losses of chromosome 1 also are unfavorable signs.30,31 

It seems quite likely that the new tyrosine kinase inhibitor treatment by Imatinib will improve the prognosis of malignant GIST, alter the natural course and modify the significance of the prognostic factors of GIST. Although this treatment was initially limited to metastatic or unresectable GISTs only, its application as a neoadjuvant therapy is included in some of the newer clinical trials.7  The information obtained from pre-Imatinib series of GISTs may be helpful guide to the application of this new therapy.

References

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