Rajani B, Smith TA, Reith JD, Goldblum JR: Retroperitoneal Leiomyosarcomas Unassociated with the Gastrointestinal Tract: A Clinicopathologic Analysis of 17 Cases. Mod Pathol 1999;12:21–28.

To the Editor: In the interesting paper describing retroperitoneal leiomyosarcomas, Rajani et al. (¹) mentioned repeatedly a concept of extra-gastrointestinal gastrointestinal stromal tumors, which should be differentiated from leiomyosarcomas. However, this concept appears to be questionable from a histogenetic point of view. Gastrointestinal stromal tumors (GIST) originate from interstitial cell of Cajal, i.e., from the gastrointestinal pacemaker cell (more precisely: they differentiate toward this cell), as supported by several studies (², ³, ⁴). The occurrence of the pacemaker cell in the retroperitoneum or in other extra-gastrointestinal sites was not described until now. Consequently, we do not know the origin of possible extra-gastrointestinal GIST. One may consider two explanations for this:

• 1 The origin of GIST is represented by any cell, which is more ubiquitous and different from the gastrointestinal tract-restricted pacemaker cell. Then, GIST might arise in the extra-gastrointestinal locations.

• 2 The origin of GIST is the pacemaker cell, and therefore extragastrointestinal GISTs do not exist; and some sarcomas in extra-gastrointestinal locations may only resemble GIST. This is supported also by the studies of multiple familial GIST (⁵, ⁶). These patients had multiple gastrointestinal lesions, but none of them had any extra-gastrointestinal GISTs, which would be interpretable as a part of the multiple neoplasia (neoplastic disease of the whole pacemaker cell system).

Thus, the existence of extra-gastrointestinal GIST seems to be uncertain.

• Michal Zamecnik, M.D.

• Department of Pathology Postgraduate Medical School Bratislava, Slovak Republic

REFERENCES

1. Rajani B, Smith TA, Reith JD, Goldblum JR. Retroperitoneal leiomyosarcomas unassociated with the gastrointestinal tract: a clinicopathologic analysis of 17 cases. Mod Pathol 1999; 12: 21–28.

2. Hirota S, Isozaki K, Moriyama Y, Hashimoto K, Nishida T, Ishiguro S, et al. Gain-of-function mutation of c-kit in human gastrointestinal stromal tumors. Science 1998; 279: 577–80.

3. Kindblom LG, Remotti HE, Aldenborg F, Kindblom-Meis JM. Gastrointestinal pacemaker cell tumor. Gastrointestinal stromal tumors show phenotypic characteristics of the interstitial cells of Cajal. J Pathol 1998; 152: 1259–69.

4. Seidal T, Edvardsson H. Expression of c-kit (CD117) and Ki67 provides information about the possible cell of origin and clinical course of gastrointestinal stromal tumours. Histopathology 1999; 34: 416–24.

5. Marshall JB, Diaz-Arias AA, Bochna GS, Vogele KA. Achalasia due to diffuse esophageal leiomyomatosis and inherited as an autosomal dominant disorder. Report of a family study. Gastroenterology 1990; 98: 1358–65.

6. O'Brien P, Kapusta L, Dardick I, Axler J, Gnidec A. Multiple familial gastrointestinal autonomic nerve tumors and small intestinal neuronal dysplasia. Am J Surg Pathol 1999; 23; 198–204.

In Reply The concept of “extragastrointestinal stromal tumors” is a new one. Certainly, there have been ample data published over the past few years showing that most, if not all, gastrointestinal stromal tumors either originate from or differentiate toward interstitial cells of Cajal (¹, ²). In 1996, Reith et al. (³) reported (in abstract form) an analysis of 39 tumors that arose in the abdominal cavity that histologically closely resembled gastrointestinal stromal tumors and were unassociated with the gastrointestinal tract. These tumors did not really resemble conventional spindled or epithelioid leiomyosarcomas that arise in the soft tissues. Immunohistochemical analysis revealed that 50% were CD34-positive, but all stained strongly for CD117 (c-kit), a marker of interstitial cells of Cajal and the single best marker of gastrointestinal stromal tumors. In addition, only a minority of these tumors expressed myogenic antigens. Thus, based upon the histologic and immunophenotypic similarities to gastrointestinal stromal tumors, the authors proposed the term “extragastrointestinal stromal tumor.”

With respect to the histogenesis of such tumors, several possibilities exist. First, these tumors may have arisen from the gastrointestinal tract but subsequently became detached to lie within the abdomen. It is also possible that these tumors arise from mesenchymal elements that have the ability to recapitulate the phenotype of interstitial cells of Cajal. Regardless of their histogenesis, we believe there is evidence to support the existence of tumors that are histologically and immunophenotypically indistinguishable from gastrointestinal stromal tumors that arise in extragastrointestinal sites.

• John R. Goldblum, M.D.

• The Cleveland Clinic Foundation Cleveland, Ohio

• J. D. Reith

• University of Florida Gainesville, Florida

• S. W. Weiss

• Emory University Atlanta, Georgia

REFERENCES

1. Kindblom LG, Remotti HE, Aldenborg F, Meis-Kindblom JM. Gastrointestinal pacemaker cell tumor (GIPACT): gastrointestinal stromal tumors show phenotypic characteristics of the interstitial cells of Cajal. Am J Pathol 1998; 152: 1259–69.

2. Seidal T, Edvardsson H. Expression of c-kit (CD117) and Ki67 provides information about the possible cell of origin and clinical course of gastrointestinal stromal tumors. Histopathology 1999; 34: 416–24.

3. Reith JD, Goldblum JR, Weiss SW. Extragastrointestinal stromal tumors: an analysis of 39 cases [abstract]. Mod Pathol 1996; 9: 51A.