| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Abstract
Gastrointestinal stromal tumors (GIST), KIT-positive and KIT signaling driven or platelet-derived growth factor receptor 
(PDGFRA) signaling driven mesenchymal tumors, are poorly known in nonhuman primates. Availability of KIT- and PDGFRA-inhibitor drug imatinib mesylate has greatly raised the interest for these tumors. At necropsy of a 22-year-old male chimpanzee, a round, firm 2-cm intramural tumor was incidentally found in the midbody of the stomach and diagnosed as a GIST. Histologically, the mass was composed of spindle to polygonal epithelioid cells arranged in short to intermediate-length, interlacing streams, bundles, and nodular whorls often separated by hyalinized eosinophilic matrix. The mitotic rate was a maximum 1/50 high-power field. Immunohistochemically, the tumor cells were diffusely positive for KIT and CD34, focally positive for -smooth muscle actin, and negative for muscle specific actin, desmin, S-100 protein, synaptophysin, and glial fibrillary acidic protein. Because the majority of human GISTs have gain-of-function KIT or PDGFRA mutations, genomic sequences of KIT exons 9, 11, 13, and 17 and PDGFRA exons 12 and 18 from this chimpanzee GIST were polymerase chain reaction amplified and sequenced. However, no mutation was identified in the analyzed "mutational hot spots." This study is the first extensive histomorphologic, immunohistochemical, and molecular genetic analysis of a chimpanzee GIST. More cases of nonhuman primate GISTs should be analyzed to discover the clinicopathologic spectrum of GISTs in these species.
Key words: Chimpanzee; gastrointestinal stromal tumors; KIT; platelet-derived growth factor receptor.
In humans, gastrointestinal stromal tumors (GISTs) are mesenchymal tumors of the gastrointestinal (GI) tract that are defined by specific morphologic, immunohistochemical, and molecular genetic features. Historically, a great majority of GISTs have been diagnosed as GI smooth muscle tumors, such as leiomyomas, leiomyoblastomas, leiomyosarcomas, and GI schwannomas. However, the lack of typical smooth muscle or Schwann-cells features prompted the classification of such tumors in the histogenetically neutral category of GIST. However, these tumors often expressed CD34, the hematopoietic progenitor cell antigen, a transmembrane protein of unknown function.20 Recently, the term GIST has become widely accepted for GI mesenchymal tumors with characteristic histologic, immunohistochemical, and genetic features. On the basis of phenotypic similarities, GISTs are believed to develop from the interstitial cells of Cajal (ICC) or their progenitor cells.20
GISTs show spindle-cell, epithelioid, and rarely pleomorphic cellular patterns, express KIT and carry KIT or platelet-derived growth factor receptor (PDGFRA) gain-of-function mutations. KIT, a receptor tyrosine kinase (TK) whose ligand is stem cell factor, and PDGFRA are two members of the type-III TK receptor family. Activation of these receptors subsequently activates networks of signal transduction pathways involved in regulation of important cell functions including promotion of proliferation and inhibition of apoptosis. Pathologic, mutational activation of TK receptor signaling pathways is considered to be a driving force in the GIST pathogenesis.8–10,20 Studies on clinically advanced, metastatic GISTs have shown that successful inhibition of pathologically activated TK receptors by imatinib mesylate (Gleevec, STI571; Novartis, Basel, Switzerland) is an effective therapeutic approach in GIST treatment.4
Recently, tumors showing similar immunohistochemical and molecular genetic profiles as human GISTs have been reported in dogs6 and horses.3,7 However, little is known regarding GISTs in other animals, including nonhuman primates. Although several studies reported GI mesenchymal tumors, leiomyomas,15,21 leiomyosarcomas,2,15 unspecified sarcomas,5,17 and gastric stromal tumors1 in nonhuman primates (Table 1), expression of KIT and CD34 and mutational status of KIT and PDGFRA were not studied in these cases, thus making comparison with human GIST difficult.
|
A hepatitis C virus–infected 22-year-old male chimpanzee was found dead in his cage, during the morning rounds. At necropsy, the animal was diagnosed with a severe cardiomyopathy. Incidental to the cause of death was a round, raised, inward and outward bulging, firm 2-cm tumor in the midbody of the stomach.
Representative tumor samples were formalin fixed and paraffin embedded (FFPE). Histologic sections (5 µm) were stained with hematoxylin and eosin (HE). Sections of the tumor were also evaluated immunohistochemically for the expression of KIT (CD117), hematopoietic progenitor cell antigen (CD34), -smooth muscle actin (SMA), muscle-specific actin (MSA), desmin (DES), S-100 protein, synaptophysin, and glial fibrillary acidic protein (GFAP). All reactions were completed according to previously published procedures.6
Expanding the tunica muscularis and extending to the sub-mucosa was a 2 cm in diameter, unencapsulated, well-circumscribed, moderately cellular neoplasm that elevated the gastric mucosa and serosa (Fig. 1). However, the mucosa was not ulcerated. The neoplasm was composed of spindle to polygonal epithelioid cells arranged in short to intermediate-length, interlacing streams, bundles, and nodular whorls often separated by hyalinized eosinophilic matrix (Fig. 2a). Tumor cells had indistinct borders with moderate amounts of pale, fibrillary, eosinophilic cytoplasm often containing a single, 3–6 µm clear perinuclear vacuole (Fig. 2a). Nuclei were round to elongated with finely stippled chromatin and indistinct nucleoli. The mitotic rate was low, 1/50 high-power field (HPF). Tumor cells were diffusely, although weakly, positive for KIT (Fig. 2b), strongly positive for CD34 (Fig. 2c, d), and focally positive for -SMA. No immunoreactivity was seen for MSA, DES, S-100 protein, synaptophysin, and GFAP.
|
In this study, the tumor located in the midbody of the stomach of the 22-year-old chimpanzee was evaluated using a spectrum of histologic, immunohistochemical, and molecular genetic techniques that led to a diagnosis of a GIST similar to those reported in humans.
In humans, GISTs are the most common mesenchymal tumors of the GI tract. These tumors can occur from the distal esophagus to the anus but most frequently involve the stomach. Several histologic patterns have been identified in human GISTs. The most common is a spindle-cell pattern (60–70%), followed by the epithelioid (20–30%), and a rare pleomorphic (<5%) one. Neoplastic cells often grow between preexisting bundles of smooth muscle, creating a micronodular pattern. Most GISTs are highly cellular and have a more basophilic appearance than leiomyomas. A perinuclear vacuole is considered a common feature. The mitotic rate varies from zero to extremely high (more than 100) per 50 HPF. GIST tumor cells are multifocally separated by an eosinophilic, amorphous, often hyalinized matrix. Nuclear palisades that resemble Verocay bodies seen in schwannomas are also a common feature. Epithelioid GISTs within the stomach correspond to the previous designation of leiomyoblastoma.20
The histomorphology of this chimpanzee tumor showed features within the spectrum of human gastric GISTs: moderately cellular expansile tumor composed of spindle and epithelioid cells, perinuclear vacuoles, eosinophilic hyalinized matrix, diffuse but weak KIT expression and strong CD34 expression.
Diffuse, strong KIT expression is a key diagnostic marker for human GIST. However, some tumors, particularly the ones with epithelioid pattern or those with PDGFRA mutations, may show weak KIT expression or do not express KIT at all.12 Expression of CD34, documented in 70–80% of human GISTs, is also considered an important GIST diagnostic marker.20 Focal positivity for -SMA seen in this chimpanzee tumor is consistent with previous studies on expression of -SMA in human GIST20 and likely support the hypothesis that GIST may develop from a pluripotential ICC or its progenitor cell that can differentiate to smooth muscle cells.22
In human GISTs, size and mitotic rate are two important criteria used commonly for prediction of clinical behavior. Small, 
2 cm tumors with negligible mitotic activity (<1/50 HPF) are largely benign in all GI locations.18,19 On the basis of these criteria, 2-cm chimpanzee gastric GISTs with low mitotic rate (1/50HPF) reported in this study belong to the benign subset of GIST.
Alteration of KIT and other TK receptors signaling pathways is considered to be an early molecular event leading to the development of several human and animal malignancies.10,14,16,20,24 In GISTs, gain-of-function mutations affect two TK receptors, KIT and PDGFRA, causing activation (auto-phosphorylation) of these receptors independent of the ligand-binding signals.8,10 KIT and PDGFRA mutations are mutually exclusive and represent two different alternative oncogenic events, leading to similar biological consequences.8
Six mutational hot spots including KIT exons 11 (juxta-membrane domain), 9 (extracellular domain), 13, and 17 (TK domains) and PDGFRA exons 18 (TK domain) and 12 (juxtamembrane domain) have been reported in human GISTs.20 Constitutive KIT exon 11, 13, and 17 mutations were reported in human familial GISTs.20 More recently, a mouse GIST model was developed, in which knock-in induction of KIT exon 11–activating mutation led to the formation of GI mesenchymal tumors indistinguishable from human GISTs supporting the crucial role of KIT mutation in GIST pathogenesis.22
In this study, chimpanzee KIT and PDGFRA genomic sequences were screened for mutational hot spots in human GISTs; however, no mutation was identified. Although a great majority of human GISTs carry specific KIT or PDGFRA mutations, there is a subset of "mutation negative tumors" including GIST in neurofibromatosis type-1 patients.8,11,12 In these tumors, KIT or PDGFRA may be activated by mutations targeting different gene regions. However, other molecular mechanisms leading to tumor development cannot be excluded.
In conclusion, this report demonstrates that the diagnostic tools used to classify human GISTs can also be used in comparative pathologic studies. Evaluation of more nonhuman primate GISTs is necessary to better understand their frequency, specific features, and pathogenetic mechanisms.
Acknowledgments
We thank Mr. Andy Morataya for photographic support.
Footnotes
The opinions or assertions contained in this study are the private views of the authors and are not to be construed as official or as reflecting the views of the Department of the Army or the Department of Defense. 
References
CiteULike 
Complore 
Connotea 
Del.icio.us 
Digg 
Facebook 
Reddit 
Technorati 
Twitter What's this?
This article has been cited by other articles:
|
|
 |
|
  K. B. Muravnick, E. J. Parente, and F. D. Piero An atypical equine gastrointestinal stromal tumor J Vet Diagn Invest, May 1, 2009; 21(3): 387 - 390. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
