**Gastrointestinal Stromal Tumours: A Contemporary Review on Pathogenesis, Morphology and Prognosis**

Muna Sabah *Connolly Hospital, Dublin, Ireland* 

## **1. Introduction**

174 Soft Tissue Tumors

Virtanen, A., E. Pukkala & A. Auvinen (2007). Angiosarcoma after radiotherapy: a cohort

Ward, H., L. E. Fox, M. B. Calderwood-Mays, A. S. Hammer & C. G. Couto (1994).

Weihrauch, M., A. Markwarth, G. Lehnert, C. Wittekind, R. Wrbitzky & A. Tannapfel (2002).

Weiss, S. W. & F. M. Enzinger (1982). Epithelioid hemangioendothelioma: a vascular tumor

Weisse, C., N. Soares, M. W. Beal, M. A. Steffey, K. J. Drobatz & C. J. Henry (2005). Survival

Withrow, S. & E. G. MacEwen (1996). *Small Animal Clinical Oncology*. Philadelphia, W.B.

Wong, K. F., C. C. So, N. Wong, L. L. Siu, Y. L. Kwong & J. K. Chan (2001). Sinonasal

Yang, X. J., J. W. Zheng, Q. Zhou, W. M. Ye, Y. A. Wang, H. G. Zhu, L. Z. Wang & Z. Y.

Yonemaru, K., H. Sakai, M. Murakami, A. Kodama, T. Mori, T. Yanai, K. Maruo & T. Masegi

Young, R. J., N. J. Brown, M. W. Reed, D. Hughes & P. J. Woll (2010). Angiosarcoma. *Lancet* 

Yuen, P. H., C. M. Matherne & L. M. Molinari-Storey (1991). SV7, a molecular clone of

Zanetta, L., M. Corada, M. Grazia Lampugnani, A. Zanetti, F. Breviario, L. Moons, P.

Zu, Y., M. A. Perle, Z. Yan, J. Liu, A. Kumar & J. Waisman (2001). Chromosomal

growth and hemorrhagic complications. *Thromb Haemost* 93(6): 1041-6. Zindy, F., L. M. Nilsson, L. Nguyen, C. Meunier, R. J. Smeyne, J. E. Rehg, C. Eberhart, C. J.

tumors in Ink4c/p53-null mice. *Cancer Res* 63(17): 5420-7.

*Immunohistochem Mol Morphol* 9(1): 24-8.

study of 8 consecutive patients. *Int J Oral Maxillofac Surg* 39(6): 568-72. Yap, J., P. J. Chuba, R. Thomas, A. Aref, D. Lucas, R. K. Severson & M. Hamre (2002).

Cutaneous hemangiosarcoma in 25 dogs: a retrospective study. *J Vet Intern Med*

Abnormalities of the ARF-p53 pathway in primary angiosarcomas of the liver. *Hum* 

times in dogs with right atrial hemangiosarcoma treated by means of surgical resection with or without adjuvant chemotherapy: 23 cases (1986-2000). *J Am Vet* 

angiosarcoma with marrow involvement at presentation mimicking malignant lymphoma: cytogenetic analysis using multiple techniques. *Cancer Genet Cytogenet*

Zhang (2010). Angiosarcomas of the head and neck: a clinico-immunohistochemical

Sarcoma as a second malignancy after treatment for breast cancer. *Int J Radiat Oncol* 

(2007). The significance of p53 and retinoblastoma pathways in canine

Moloney murine sarcoma virus 349, transforms vascular endothelial cells. *Am J* 

Carmeliet, M. S. Pepper & E. Dejana (2005). Downregulation of vascular endothelial-cadherin expression is associated with an increase in vascular tumor

Sherr & M. F. Roussel (2003). Hemangiosarcomas, medulloblastomas, and other

abnormalities and p53 gene mutation in a cardiac angiosarcoma. *Appl* 

study of 332,163 Finnish cancer patients. *Br J Cancer* 97(1): 115-7.

often mistaken for a carcinoma. *Cancer* 50(5): 970-81.

8(5): 345-8.

*Pathol* 33(9): 884-92.

*Med Assoc* 226(4): 575-9.

*Biol Phys* 52(5): 1231-7.

*Oncol* 11(10): 983-91.

*Pathol* 139(6): 1449-61.

hemangiosarcoma. *J Vet Med Sci* 69(3): 271-8.

Saunders Co.

129(1): 64-8.

Gastrointestinal stromal tumours (GISTs) comprise the largest subset of mesenchymal tumours of the digestive tract. Over the past 10 years, this group of tumours has emerged from a poorly understood neoplasm to a well defined tumour entity.

The first accurate description of mesenchymal neoplasms of the gastrointestinal tract was in 1941 (Golden T & Stout AP, 1941). Traditionally, these tumours were thought to be derived from smooth muscle cells, based on their resemblance to smooth muscle tumours. They were referred to as leiomyomas, bizarre leiomyomas (Stout AP, 1976), cellular leiomyomas (Appelman, 1977) and leiomyosarcomas. However, the advent of electron microscopy revealed that only a few of them have convincing ultrastructural evidence of smooth muscle differentiation. In addition, the application of immunohistochemistry clearly demonstrated that many of these tumours lack the features of smooth muscle differentiation. This led Mazur and Clark in 1983 to introduce the generic designation "stromal tumour" (Mazur & Clark, 1983).

A little later, in 1984, Herrera et al (Herrera et al., 1984) introduced the concept of "plexosarcoma" to acknowledge the existence of a small subset of stromal tumours with autonomic neuronal differentiation which became better known as gastrointestinal autonomic nerve tumours (GANTs) (Lauwers et al., 1993).

A considerable controversy arose as to the line of differentiation these tumours take. Some tumours exhibit a myogenic phenotype, while others may show a neural differentiation, mixed or no differentiation at all, the so called "null phenotype". Some enthusiasm was generated by the recognition that a significant proportion of stromal tumours express CD34 (Miettinen et al., 1995). However the diagnostic utility of this marker was hampered by its poor specificity. As a consequence of the lack of reproducible diagnostic criteria, GIST represented a generic term that indicates any mesenchymal tumour arising in the gastrointestinal tract.

The recognition of the central role of *c-kit* mutations in the pathogenesis of GISTs (Hirota et al., 1998; Rubin et al., 2000) and in most cases the associated expression of KIT protein in these tumours has provided a reproducible genotypic and phenotypic marker (Kindblom et al., 1998). Therefore KIT (CD117 in the standardised terminology of leucocyte antigens) expression has emerged as a marker for discriminating GISTs from other mesenchymal

Gastrointestinal Stromal Tumours:

2002) (Figure 1A).

2004; Hirota et al., 1998).

reported (Heinrich et al., 2003a).

2004; Willmore et al., 2004).

**3.2** *PDGFRA* **mutations** 

al., 2005; Heinrich et al., 2003b).

A Contemporary Review on Pathogenesis, Morphology and Prognosis 177

contains a total of 21 exons. However, mutations cluster within only four exons. They are in decreasing order of frequency, exon 11 encoding the intracellular juxtamembrane domain, exon 9 encoding the extracellular domain , exon 13 encoding the first portion of the kinase domain and exon 17 encoding the kinase activation loop (Giuly et al., 2003; Heinrich et al.,

Mutations affecting exon 11 have been reported in 60-70% of GISTs (Corless et al., 2002; Corless et al., 2004; Heinrich et al., 2003a; Hirota et al., 1998; Rubin et al., 2001). The juxtamembrane region exerts a negative regulatory effect on KIT receptor (Longley et al., 2001) and therefore mutations in this region lead to loss of its inhibitory function. Mutations in exon 11 are fairly heterogenous and different types of mutations cluster within different

Approximately 60-70% of exon 11 mutations are in-frame deletions of 1 to several codons and the majority occur at the 5' and cluster between codons Gln550 and Glu561 (Corless et al.,

Missense point mutations in exon 11 occur in 20-30% of GISTs. They affect codons Trp557, Val559 and Val560 and Leu576. Internal tandem duplications are found at the 3' end of the exon (codon 576-580) (Lasota et al., 2003a; Lasota & Miettinen, 2006; Rubin, 2006) and are

Exon 9 mutations are found in approximately 10% of cases (Antonescu et al., 2003; Hirota et al., 2001; Lasota et al., 2000b; Lux et al., 2000; Sakurai et al., 2001). Nearly all mutations affecting exon 9 are insertion of six nucleotides that result in Ala502-Tyr503 duplication at the protein level (Heinrich et al., 2003a; Hostein et al., 2006; Lasota et al., 2000b; Lasota et al., 2003a; Lux et al., 2000; Willmore et al., 2004). This type of mutation is associated with small intestinal localisation and aggressive behaviour (Antonescu et al., 2003; Antonescu, 2006; Corless et al., 2004; Lasota et al., 2003a). Patients with this type of mutation respond less well to imatinib. More recently, another duplication leading to Phe506-Phe508 duplication was

Mutations affecting exon 13 occur in approximately 1% of GISTs (Heinrich et al., 2003a; Kinoshita et al., 2003; Lasota et al., 2000b; Lux et al., 2000). All exon 13 mutations identified to date are missense mutations resulting in substitution of Glu for Lys642 (Lasota et al., 2000b; Lux et al., 2000) and are associated with resistance to imatinib treatment (Chen et al.,

Mutations affecting exon 17 are very rare and are found in less than 1% of all GISTs (Heinrich et al., 2003a; Rubin et al., 2001) and are typically missense substitution at codons 820 and 822 (Tornillo & Terracciano, 2006), whereas mutations at codon 817 are usually observed in non GISTs, including seminomas and mastocytomas (Corless et al., 2004).

Approximately 5%-10% of GISTs have mutations within *PDGFRA* (Corless et al., 2005; Heinrich et al., 2003b; Hirota et al., 2003). These mutations are functionally similar to *c-ki*t mutations and are usually seen in epithelioid, gastric GISTs which show weak or no immunoreactivity for KIT (Corless, 2004; Corless et al., 2004; Corless et al., 2005; Heinrich et al., 2003a; Hornick & Fletcher, 2007; Lasota et al., 2004; Medeiros et al., 2004). Three different regions of *PDGFRA* have been reported to be mutated in GISTs (Figure 1B). These mutations, in decreasing order of frequency affect exon 18, exon 12 and exon 14 (Corless et

regions. These mutations correlate with the best response to imatinib.

typically seen in gastric GISTs (Lasota & Miettinen, 2006).

gastrointestinal neoplasms and some have equated immunoreactivity for KIT as definition of GISTs (Miettinen & Lasota, 2001).

Recently, it has become apparent that some GISTs that lacked *c-ki*t mutations were found to have activating mutations of *PDGFRA*. Therefore GISTs can be defined as specific CD117 positive and *c-kit* or *PDGFRA* mutation-driven mesenchymal tumours of the gastrointestinal tract.

## **2. Histogenesis**

GISTs are either derived from or differentiate towards the interstitial cell of Cajal (ICC), or their stem cell precursors which have the capacity to differentiate towards both the ICC and smooth muscle phenotype (Kindblom et al., 1998; Rubin et al., 2000). The ICCs are intercalated between the autonomic nerves and smooth muscle cells. Their principle function is to generate autonomous rhythmic contractions, involved in digestion and peristalsis. Therefore these cells are known as the "pacemaker" cells of the gastrointestinal tract.

Morphologically, these cells are slender with ovoid nuclei and scanty cytoplasm. They have incomplete features of both neural and myoid differentiation.

Immunohistochemical studies revealed that GISTs have similar features to ICC, being positive with CD34 and CD117 and negative or variably positive for other neural and smooth muscle markers (Kindblom et al., 1998).

## **3. Molecular biology (***c-kit* **and** *PDGFRA***)**

The *c-kit* proto-oncogene is a cellular homolog of the *v-kit* oncogene present in the genome of Hardy-Zuckerman-feline sarcoma virus (Besmer et al., 1986). It encodes a transmembrane tyrosine kinase receptor (Vliagoftis et al., 1997). The ligand for KIT is a growth factor called the stem cell factor.

Extracellular binding of stem cell factor results in dimerisation of the receptor, triggering phosphorylation of the kinase domain. This induces a signalling cascade that propagates through the cytoplasm into the nucleus. This signalling cascade affects many aspects of cellular behaviour including proliferation, differentiation, adhesion and apoptosis (Vliagoftis et al., 1997).

KIT expression is extremely important in the development of several cell types including the haematopoietic stem cells, mast cells, germ cells, melanocytes, some epithelial cells and the ICC (Vliagoftis et al., 1997).

The majority of GISTs have gain of function mutations of *c-kit* (Corless et al., 2004). These mutations have been observed in sporadic GISTs and less commonly as germline mutations in familial GISTs (Hirota et al., 1998; Isozaki et al., 2000), suggesting that constitutive expression of KIT plays a significant role in the tumourigenesis of GISTs. However, around 10-15% of GISTs lack *c-kit* mutations (Debiec-Rychter et al., 2004b). Within this group a large subset would have gain of function mutations of *PDGFRA* (Heinrich et al., 2003a; Heinrich et al., 2003b; Hirota et al., 2003).

## **3.1** *c-kit* **mutations**

Approximately 85%-90%of sporadic GISTs harbour a mutation of *c-kit* (Corless et al., 2002; Heinrich et al., 2002; Heinrich et al., 2003a; Hirota et al., 1998; Rubin et al., 2001). *c-kit* 

gastrointestinal neoplasms and some have equated immunoreactivity for KIT as definition

Recently, it has become apparent that some GISTs that lacked *c-ki*t mutations were found to have activating mutations of *PDGFRA*. Therefore GISTs can be defined as specific CD117 positive and *c-kit* or *PDGFRA* mutation-driven mesenchymal tumours of the gastrointestinal

GISTs are either derived from or differentiate towards the interstitial cell of Cajal (ICC), or their stem cell precursors which have the capacity to differentiate towards both the ICC and smooth muscle phenotype (Kindblom et al., 1998; Rubin et al., 2000). The ICCs are intercalated between the autonomic nerves and smooth muscle cells. Their principle function is to generate autonomous rhythmic contractions, involved in digestion and peristalsis. Therefore these cells are known as the "pacemaker" cells of the gastrointestinal

Morphologically, these cells are slender with ovoid nuclei and scanty cytoplasm. They have

Immunohistochemical studies revealed that GISTs have similar features to ICC, being positive with CD34 and CD117 and negative or variably positive for other neural and

The *c-kit* proto-oncogene is a cellular homolog of the *v-kit* oncogene present in the genome of Hardy-Zuckerman-feline sarcoma virus (Besmer et al., 1986). It encodes a transmembrane tyrosine kinase receptor (Vliagoftis et al., 1997). The ligand for KIT is a growth factor called

Extracellular binding of stem cell factor results in dimerisation of the receptor, triggering phosphorylation of the kinase domain. This induces a signalling cascade that propagates through the cytoplasm into the nucleus. This signalling cascade affects many aspects of cellular behaviour including proliferation, differentiation, adhesion and apoptosis

KIT expression is extremely important in the development of several cell types including the haematopoietic stem cells, mast cells, germ cells, melanocytes, some epithelial cells and the

The majority of GISTs have gain of function mutations of *c-kit* (Corless et al., 2004). These mutations have been observed in sporadic GISTs and less commonly as germline mutations in familial GISTs (Hirota et al., 1998; Isozaki et al., 2000), suggesting that constitutive expression of KIT plays a significant role in the tumourigenesis of GISTs. However, around 10-15% of GISTs lack *c-kit* mutations (Debiec-Rychter et al., 2004b). Within this group a large subset would have gain of function mutations of *PDGFRA* (Heinrich et al., 2003a; Heinrich

Approximately 85%-90%of sporadic GISTs harbour a mutation of *c-kit* (Corless et al., 2002; Heinrich et al., 2002; Heinrich et al., 2003a; Hirota et al., 1998; Rubin et al., 2001). *c-kit* 

incomplete features of both neural and myoid differentiation.

smooth muscle markers (Kindblom et al., 1998).

**3. Molecular biology (***c-kit* **and** *PDGFRA***)** 

of GISTs (Miettinen & Lasota, 2001).

tract.

tract.

**2. Histogenesis** 

the stem cell factor.

(Vliagoftis et al., 1997).

ICC (Vliagoftis et al., 1997).

et al., 2003b; Hirota et al., 2003).

**3.1** *c-kit* **mutations** 

contains a total of 21 exons. However, mutations cluster within only four exons. They are in decreasing order of frequency, exon 11 encoding the intracellular juxtamembrane domain, exon 9 encoding the extracellular domain , exon 13 encoding the first portion of the kinase domain and exon 17 encoding the kinase activation loop (Giuly et al., 2003; Heinrich et al., 2002) (Figure 1A).

Mutations affecting exon 11 have been reported in 60-70% of GISTs (Corless et al., 2002; Corless et al., 2004; Heinrich et al., 2003a; Hirota et al., 1998; Rubin et al., 2001). The juxtamembrane region exerts a negative regulatory effect on KIT receptor (Longley et al., 2001) and therefore mutations in this region lead to loss of its inhibitory function. Mutations in exon 11 are fairly heterogenous and different types of mutations cluster within different regions. These mutations correlate with the best response to imatinib.

Approximately 60-70% of exon 11 mutations are in-frame deletions of 1 to several codons and the majority occur at the 5' and cluster between codons Gln550 and Glu561 (Corless et al., 2004; Hirota et al., 1998).

Missense point mutations in exon 11 occur in 20-30% of GISTs. They affect codons Trp557, Val559 and Val560 and Leu576. Internal tandem duplications are found at the 3' end of the exon (codon 576-580) (Lasota et al., 2003a; Lasota & Miettinen, 2006; Rubin, 2006) and are typically seen in gastric GISTs (Lasota & Miettinen, 2006).

Exon 9 mutations are found in approximately 10% of cases (Antonescu et al., 2003; Hirota et al., 2001; Lasota et al., 2000b; Lux et al., 2000; Sakurai et al., 2001). Nearly all mutations affecting exon 9 are insertion of six nucleotides that result in Ala502-Tyr503 duplication at the protein level (Heinrich et al., 2003a; Hostein et al., 2006; Lasota et al., 2000b; Lasota et al., 2003a; Lux et al., 2000; Willmore et al., 2004). This type of mutation is associated with small intestinal localisation and aggressive behaviour (Antonescu et al., 2003; Antonescu, 2006; Corless et al., 2004; Lasota et al., 2003a). Patients with this type of mutation respond less well to imatinib. More recently, another duplication leading to Phe506-Phe508 duplication was reported (Heinrich et al., 2003a).

Mutations affecting exon 13 occur in approximately 1% of GISTs (Heinrich et al., 2003a; Kinoshita et al., 2003; Lasota et al., 2000b; Lux et al., 2000). All exon 13 mutations identified to date are missense mutations resulting in substitution of Glu for Lys642 (Lasota et al., 2000b; Lux et al., 2000) and are associated with resistance to imatinib treatment (Chen et al., 2004; Willmore et al., 2004).

Mutations affecting exon 17 are very rare and are found in less than 1% of all GISTs (Heinrich et al., 2003a; Rubin et al., 2001) and are typically missense substitution at codons 820 and 822 (Tornillo & Terracciano, 2006), whereas mutations at codon 817 are usually observed in non GISTs, including seminomas and mastocytomas (Corless et al., 2004).

### **3.2** *PDGFRA* **mutations**

Approximately 5%-10% of GISTs have mutations within *PDGFRA* (Corless et al., 2005; Heinrich et al., 2003b; Hirota et al., 2003). These mutations are functionally similar to *c-ki*t mutations and are usually seen in epithelioid, gastric GISTs which show weak or no immunoreactivity for KIT (Corless, 2004; Corless et al., 2004; Corless et al., 2005; Heinrich et al., 2003a; Hornick & Fletcher, 2007; Lasota et al., 2004; Medeiros et al., 2004). Three different regions of *PDGFRA* have been reported to be mutated in GISTs (Figure 1B). These mutations, in decreasing order of frequency affect exon 18, exon 12 and exon 14 (Corless et al., 2005; Heinrich et al., 2003b).

Gastrointestinal Stromal Tumours:

gastrointestinal tract.

et al., 2007).

**5. GISTs syndromes** 

tumour syndromes. These include:

**5.2 Carney's triad and Carney Stratakis syndrome** 

may develop many years after the occurrence of GIST.

the pathogenesis of Carney Stratakis syndrome (Pasini et al., 2008).

**5.3 Neurofibromatosis type 1 (von Recklinghausen's disease)** 

**5.1 Familial GIST syndrome** 

A Contemporary Review on Pathogenesis, Morphology and Prognosis 179

older individuals (Nilsson et al., 2005; Tran et al., 2005). There is no gender preference except in the setting of Carney's triad (Carney, 1999). Although there are no known predisposing risk factors, there are reports of familial GISTs (Isozaki et al., 2000) and GISTs in association with

Although GISTs may arise anywhere in the gastrointestinal tract, they are most common in the stomach (60%), followed by the jejenum and ileum (30%), duodenum (5%) and colorectum (<5%) (Miettinen & Lasota, 2006a; Miettinen & Lasota, 2006b). Very few cases have been described in the oesophagus (Miettinen et al., 2000a) or appendix (Miettinen & Sobin, 2001). A small proportion of GISTs arise in extra-gastrointestinal tract sites including the omentum, mesentery and retroperitoneum (Miettinen et al., 1999) with a few case reports of primary GISTs occurring in the gallbladder, pancreas, liver and urinary bladder (Bussolati, 2005; Hu et al., 2003; Lasota et al., 2000a; Mendoza-Marin et al., 2002). It is important to make sure that these do not represent spread from a primary lesion in the

Although the vast majority of GISTs are sporadic, approximately 5% are associated with

This syndrome is inherited as an autosomal dominant disease. Patients with familial GISTs have germline activating mutations involving c*-kit* (Hirota et al., 2000; Isozaki et al., 2000; Li et al., 2005; Maeyama et al., 2001; Nishida et al., 1998; O'Brien et al., 1999) or *PDGFRA* (Chompret et al., 2004). These patients develop multiple GISTs, some of which in association with hyperplasia of the ICC (Chen et al., 2002). Other patients may also have the clinical manifestations of *c-kit* activation such as mastocytosis and hyperpigmentation (Kang

Carney's triad consists of multicentric functioning extra-adrenal paraganglioma, pulmonary chondroma and multifocal epithelioid GIST of the stomach (Carney, 1999). There is a striking female predominance with approximately 85% of cases occurring in females. Most patients are less than 30 years of age at the time of diagnosis. Only subsets of patients have all of the three tumour types. Extra-adrenal pargangliomas and pulmonary chondromas

Carney Stratakis syndrome is a recently recognised autosomal dominant syndrome which represents a separate condition that affects both males and females and lacks the association with pulmonary chondromas. Mutations of the genes coding for succinate dehydrogenase subunits, typically associated with familial paragangliomas, are most likely implicated in

Mutations of *c-kit* or *PDGFRA* have not been identified in patients with Carney's triad or Carney Stratakis syndrome (Corless et al., 2004; Matyakhina et al., 2007; Prakash et al., 2005).

Some patients with classic neurofibromatosis type 1 develop GISTs (Giuly et al., 2003; Takazawa et al., 2005). The tumours are usually in the small bowel and often multifocal.

Von Recklinghausen's disease (Giuly et al., 2003), pointing to a genetic role.

Exon 18 encodes the kinase activation loop (TK2). The majority of exon 18 mutations are missense mutations leading to substitution of Val for Asp842. These mutations are usually seen in gastric tumours and are associated with resistance to imatinib (Heinrich et al., 2003a; Heinrich et al., 2003b; Hirota et al., 2003; Hornick & Fletcher, 2007; Ohashi et al., 2004).

Exon 12 encodes the juxtamembrane. Mutations affecting exon 12 are rare and lead to Asp for Val561 substitution. In-frame deletions and insertions have also been reported around codon Val561 (Corless et al., 2005; Miettinen & Lasota, 2006b).

Exon 14 encodes the kinase I domain (TK1). A single missense mutation leading to substitution of Lys for Asn659 has been described (Corless et al., 2005).

Approximately 5-10% of GISTs are negative for both *c-kit* and *PDGFRA* mutations. This subset of GISTs may have an activating mutation either in a tyrosine kinase receptor similar to KIT and PDGFRA or in downstream signalling molecule of KIT or PDGFRA signalling cascade (Hornick & Fletcher, 2007; Rubin, 2006).

Fig. 1. Mutations of *c-kit* and *PDGFRA*.

#### **3.3** *DOG1* **gene**

*DOG1* "discovered on GIST" is a new gene, which encodes a protein of unknown function. It is expressed in GISTs independent of mutation type and is absent in non GISTs (West et al., 2004).

#### **4. Epidemiology and risk factors**

The lack of accepted diagnostic criteria for GISTs has led to variations in the current estimate of disease incidence. GIST is a relatively rare neoplasm representing less than 1% of all primary tumours of the gastrointestinal tract with an incidence of approximately 0.68- 1.45/100,000 (Miettinen & Lasota, 2001; Nilsson et al., 2005; Tran et al., 2005). These figures do not account for benign GISTs, which are usually not included in cancer registries and are usually lost to clinical follow-up. Disease incidence seems to be uniform across all geographic and ethnic populations. More than 90% of GISTs occur in adults, mostly in middle-aged or older individuals (Nilsson et al., 2005; Tran et al., 2005). There is no gender preference except in the setting of Carney's triad (Carney, 1999). Although there are no known predisposing risk factors, there are reports of familial GISTs (Isozaki et al., 2000) and GISTs in association with Von Recklinghausen's disease (Giuly et al., 2003), pointing to a genetic role.

Although GISTs may arise anywhere in the gastrointestinal tract, they are most common in the stomach (60%), followed by the jejenum and ileum (30%), duodenum (5%) and colorectum (<5%) (Miettinen & Lasota, 2006a; Miettinen & Lasota, 2006b). Very few cases have been described in the oesophagus (Miettinen et al., 2000a) or appendix (Miettinen & Sobin, 2001). A small proportion of GISTs arise in extra-gastrointestinal tract sites including the omentum, mesentery and retroperitoneum (Miettinen et al., 1999) with a few case reports of primary GISTs occurring in the gallbladder, pancreas, liver and urinary bladder (Bussolati, 2005; Hu et al., 2003; Lasota et al., 2000a; Mendoza-Marin et al., 2002). It is important to make sure that these do not represent spread from a primary lesion in the gastrointestinal tract.

## **5. GISTs syndromes**

178 Soft Tissue Tumors

Exon 18 encodes the kinase activation loop (TK2). The majority of exon 18 mutations are missense mutations leading to substitution of Val for Asp842. These mutations are usually seen in gastric tumours and are associated with resistance to imatinib (Heinrich et al., 2003a; Heinrich et al., 2003b; Hirota et al., 2003; Hornick & Fletcher, 2007; Ohashi et al., 2004). Exon 12 encodes the juxtamembrane. Mutations affecting exon 12 are rare and lead to Asp for Val561 substitution. In-frame deletions and insertions have also been reported around

Exon 14 encodes the kinase I domain (TK1). A single missense mutation leading to

Approximately 5-10% of GISTs are negative for both *c-kit* and *PDGFRA* mutations. This subset of GISTs may have an activating mutation either in a tyrosine kinase receptor similar to KIT and PDGFRA or in downstream signalling molecule of KIT or PDGFRA signalling

*DOG1* "discovered on GIST" is a new gene, which encodes a protein of unknown function. It is expressed in GISTs independent of mutation type and is absent in non GISTs (West et

The lack of accepted diagnostic criteria for GISTs has led to variations in the current estimate of disease incidence. GIST is a relatively rare neoplasm representing less than 1% of all primary tumours of the gastrointestinal tract with an incidence of approximately 0.68- 1.45/100,000 (Miettinen & Lasota, 2001; Nilsson et al., 2005; Tran et al., 2005). These figures do not account for benign GISTs, which are usually not included in cancer registries and are usually lost to clinical follow-up. Disease incidence seems to be uniform across all geographic and ethnic populations. More than 90% of GISTs occur in adults, mostly in middle-aged or

codon Val561 (Corless et al., 2005; Miettinen & Lasota, 2006b).

cascade (Hornick & Fletcher, 2007; Rubin, 2006).

Fig. 1. Mutations of *c-kit* and *PDGFRA*.

**4. Epidemiology and risk factors** 

**3.3** *DOG1* **gene** 

al., 2004).

substitution of Lys for Asn659 has been described (Corless et al., 2005).

Although the vast majority of GISTs are sporadic, approximately 5% are associated with tumour syndromes. These include:

## **5.1 Familial GIST syndrome**

This syndrome is inherited as an autosomal dominant disease. Patients with familial GISTs have germline activating mutations involving c*-kit* (Hirota et al., 2000; Isozaki et al., 2000; Li et al., 2005; Maeyama et al., 2001; Nishida et al., 1998; O'Brien et al., 1999) or *PDGFRA* (Chompret et al., 2004). These patients develop multiple GISTs, some of which in association with hyperplasia of the ICC (Chen et al., 2002). Other patients may also have the clinical manifestations of *c-kit* activation such as mastocytosis and hyperpigmentation (Kang et al., 2007).

## **5.2 Carney's triad and Carney Stratakis syndrome**

Carney's triad consists of multicentric functioning extra-adrenal paraganglioma, pulmonary chondroma and multifocal epithelioid GIST of the stomach (Carney, 1999). There is a striking female predominance with approximately 85% of cases occurring in females. Most patients are less than 30 years of age at the time of diagnosis. Only subsets of patients have all of the three tumour types. Extra-adrenal pargangliomas and pulmonary chondromas may develop many years after the occurrence of GIST.

Carney Stratakis syndrome is a recently recognised autosomal dominant syndrome which represents a separate condition that affects both males and females and lacks the association with pulmonary chondromas. Mutations of the genes coding for succinate dehydrogenase subunits, typically associated with familial paragangliomas, are most likely implicated in the pathogenesis of Carney Stratakis syndrome (Pasini et al., 2008).

Mutations of *c-kit* or *PDGFRA* have not been identified in patients with Carney's triad or Carney Stratakis syndrome (Corless et al., 2004; Matyakhina et al., 2007; Prakash et al., 2005).

## **5.3 Neurofibromatosis type 1 (von Recklinghausen's disease)**

Some patients with classic neurofibromatosis type 1 develop GISTs (Giuly et al., 2003; Takazawa et al., 2005). The tumours are usually in the small bowel and often multifocal.

Gastrointestinal Stromal Tumours:

cytologic appearance.

ovoid and may be pushed to an eccentric location.

A Contemporary Review on Pathogenesis, Morphology and Prognosis 181

paraganglioma or carcinoid. The tumour cells exhibit eosinophilic or clear cytoplasm (Figure 2D). The cytoplasm may be retracted simulating inclusions. The nuclei tend to be round to

GISTs with a mixed pattern (Figure 2E) are more common in the stomach. It may feature an abrupt transition between spindle and epithelioid areas or may show intermediate ovoid

Fig. 2. Haematoxylin and Eosin sections of GISTs with a spindle cell morphology (A, B), GISTs with an epithelioid morphology (C, D), mixed cell pattern (E) and pleomorphic GIST (F).

A small minority of GISTs (<5%) have extensive nuclear pleomorphism (Figure 2F).

They tend to be small, mitotically inactive and have a bland morphology. They are often accompanied by ICC hyperplasia. Most GISTs arising in the setting of NF1 do not have *c-kit*  or *PDGFRA* mutations (Takazawa et al., 2005; Yantiss et al., 2005).

## **6. Clinical presentations**

The clinical picture of GISTs depends on site, size and aggressiveness of these tumours which can vary from the benign to frank sarcoma. The symptoms can also vary, depending on the size and location of the lesion. Small tumours may be asymptomatic and may be found incidentally at laparotomy, endoscopy or during radiological studies for other conditions. Symptomatic tumours often present with abdominal pain or discomfort. They may ulcerate and cause gastrointestinal bleeding. This may be acute or insidious leading to anaemia or fatigue. Lesions in the oesophagus may present with dysphagia, while those of the intestine may present with an abdominal mass, obstruction or perforation. Occasionally, duodenal GISTs cause obstructive jaundice.

Patients with GISTs may also present with metastases, particularly to the liver. Malignancies reported in association with GISTs include carcinomas of the gastrointestinal tract as well as those of the breast, kidney, lung, uterus and prostate (Agaimy et al., 2006; Dematteo et al., 2000).

## **7. Morphology**

#### **7.1 Gross features**

GISTs develop in any part of the gastrointestinal tract and tend to be primarily intramural tumours, usually involving the submucosa and muscularis propria.

GISTs vary in size from being several millimetres in diameter to over 30cms. Most lesions are well circumscribed, but are unencapsulated. Some are multinodular. They may have either a whorled fibroid-like cut surface or may be fleshy in appearance. They may protrude inward, leading to ulceration of the mucosa, or outward resulting in serosal based lesion. Large tumours may protrude into the lumen and from the serosa, resulting in a dumbbell appearance.

Areas of haemorrhage, cystic degeneration and central necrosis may be seen. The overlying mucosa may be intact or ulcerated, a feature that can be seen in either benign or malignant tumours.

#### **7.2 Microscopic features**

GISTs show a wide range of histologic features. Morphologically the cells of GISTs are spindle, epithelioid, mixed pattern and occasionally pleomorphic.

Spindle cell type is the predominant pattern, seen in 70% of GIST cases (Figure 2A). The tumour cells are arranged in short fascicles, whorls or a storiform growth pattern. The neoplastic cells have light fibrillary eosinophilic cytoplasm with indistinct cell borders. Perinuclear vacuoles are present and indent the nucleus at one pole (Figure 2B). These vacuoles are an artefact of fixation since they are not present in frozen sections (Appelman, 1977). The Nuclei tend to have relatively pointed ends as compared with blunt-ended nuclei in smooth muscle tumours, often with vesicular chromatin. Nuclear palisading reminiscent of that seen in schwannoma may be seen.

GISTs with epithelioid morphology account for 20% of cases (Figure 2C). The tumour cells are arranged in sheets or they may have a nested organoid growth pattern, reminiscent of

They tend to be small, mitotically inactive and have a bland morphology. They are often accompanied by ICC hyperplasia. Most GISTs arising in the setting of NF1 do not have *c-kit* 

The clinical picture of GISTs depends on site, size and aggressiveness of these tumours which can vary from the benign to frank sarcoma. The symptoms can also vary, depending on the size and location of the lesion. Small tumours may be asymptomatic and may be found incidentally at laparotomy, endoscopy or during radiological studies for other conditions. Symptomatic tumours often present with abdominal pain or discomfort. They may ulcerate and cause gastrointestinal bleeding. This may be acute or insidious leading to anaemia or fatigue. Lesions in the oesophagus may present with dysphagia, while those of the intestine may present with an abdominal mass, obstruction or perforation. Occasionally,

Patients with GISTs may also present with metastases, particularly to the liver. Malignancies reported in association with GISTs include carcinomas of the gastrointestinal tract as well as those of the breast, kidney, lung, uterus and prostate (Agaimy et al., 2006; Dematteo et al.,

GISTs develop in any part of the gastrointestinal tract and tend to be primarily intramural

GISTs vary in size from being several millimetres in diameter to over 30cms. Most lesions are well circumscribed, but are unencapsulated. Some are multinodular. They may have either a whorled fibroid-like cut surface or may be fleshy in appearance. They may protrude inward, leading to ulceration of the mucosa, or outward resulting in serosal based lesion. Large tumours may protrude into the lumen and from the serosa, resulting in a dumbbell

Areas of haemorrhage, cystic degeneration and central necrosis may be seen. The overlying mucosa may be intact or ulcerated, a feature that can be seen in either benign or malignant

GISTs show a wide range of histologic features. Morphologically the cells of GISTs are

Spindle cell type is the predominant pattern, seen in 70% of GIST cases (Figure 2A). The tumour cells are arranged in short fascicles, whorls or a storiform growth pattern. The neoplastic cells have light fibrillary eosinophilic cytoplasm with indistinct cell borders. Perinuclear vacuoles are present and indent the nucleus at one pole (Figure 2B). These vacuoles are an artefact of fixation since they are not present in frozen sections (Appelman, 1977). The Nuclei tend to have relatively pointed ends as compared with blunt-ended nuclei in smooth muscle tumours, often with vesicular chromatin. Nuclear palisading reminiscent

GISTs with epithelioid morphology account for 20% of cases (Figure 2C). The tumour cells are arranged in sheets or they may have a nested organoid growth pattern, reminiscent of

or *PDGFRA* mutations (Takazawa et al., 2005; Yantiss et al., 2005).

tumours, usually involving the submucosa and muscularis propria.

spindle, epithelioid, mixed pattern and occasionally pleomorphic.

**6. Clinical presentations** 

2000).

**7. Morphology 7.1 Gross features** 

appearance.

tumours.

**7.2 Microscopic features** 

of that seen in schwannoma may be seen.

duodenal GISTs cause obstructive jaundice.

paraganglioma or carcinoid. The tumour cells exhibit eosinophilic or clear cytoplasm (Figure 2D). The cytoplasm may be retracted simulating inclusions. The nuclei tend to be round to ovoid and may be pushed to an eccentric location.

GISTs with a mixed pattern (Figure 2E) are more common in the stomach. It may feature an abrupt transition between spindle and epithelioid areas or may show intermediate ovoid cytologic appearance.

A small minority of GISTs (<5%) have extensive nuclear pleomorphism (Figure 2F).

Fig. 2. Haematoxylin and Eosin sections of GISTs with a spindle cell morphology (A, B), GISTs with an epithelioid morphology (C, D), mixed cell pattern (E) and pleomorphic GIST (F).

Gastrointestinal Stromal Tumours:

junctions and intermediate filaments.

**9. Immunohistochemical features** 

domain of *c-kit* (Lee et al., 2001).

**8. Gastrointestinal autonomic nerve tumours** 

A Contemporary Review on Pathogenesis, Morphology and Prognosis 183

GANTs were originally designated "plexoma" and "plexosarcoma" based on ultrastructural resemblance to cells of autonomic nervous system. GANTs are uncommon tumours which can occasionally develop in the context of von Recklinghausen's disease (Lespi & Drut, 1997) and Carney's triad (Segal et al., 1994). Familial multiple GANTs have been described

The characteristic ultrastructural features include complex interdigitating cell processes with bulbulous synaptic structures, dense core neurosecretory granules, rudimentary cell

Although originally believed to be a distinct tumour, recent evidence supports the concept that GANTs represent a phenotyptic variant of GISTs (Segal et al., 1994). These tumours tend to be KIT positive and a most have gain of function mutation in the juxtamembrane

The overwhelming majority of GISTs express KIT protein (detected as CD117). The results of KIT immunostaining depend on several technical factors including fixation, tissue preparation, variations in antibody clones in terms of specificity and sensitivity, antibody dilutions and staining techniques. This may account in part for the reported immunophenotypic heterogeneity in GISTs. It has been emphasised that CD117 should be

The monoclonal antibodies currently available react inconsistently in formalin fixed paraffin

Given the potential clinical importance of CD117 immunostaining, optimisation of the

The pattern of staining is variable (Figure 4). Diffuse strong pancytoplasmic staining is the predominant pattern. Membranous staining and dot-like "golgi zone pattern" staining can be identified. It has been suggested that different staining patterns correlate with different types of *c-kit* mutations (Fletcher et al., 2002a). Stromal mast cells and ICC are useful internal

Fig. 4. Pattern of CD117 immunostaining. GIST showing membranous and cytoplasmic

embedded tissue and identify only a minority of GISTs (Miettinen et al., 2002b).

positive controls to supplement the normal positive and negative controls.

in an association with intestinal neuronal dysplasia (O'Brien et al., 1999).

performed without epitope retrieval (Fletcher & Fletcher, 2002).

staining techniques and reproducibility are critical.

staining (A) and golgi zone-like staining (B).

The stroma in GISTs may be myxoid or it may be hyalinised (Figure 3A) or calcified. Delicate thin walled blood vessels may be prominent and may be associated with stromal haemorrhage (Figure 3B). Necrosis may be present. Lymphocytes can be seen.

Gastric GISTs have spindle cell morphology in 50% of cases, while 30% are epithelioid and 20% are mixed (Miettinen et al., 2005).

Small intestinal GISTs are more often spindled and may show extracellular bright eosinophilic collagen globules termed "skenoid fibres" (Figure 3C). These structures are periodic acid-Schiff (PAS) positive (Figure 3D). Small bowel tumours with an epithelioid morphology are usually associated with an aggressive behaviour.

Studies on oesophageal, colonic, ano-rectal and extra-gastrointestinal GISTs are sparse. Oesophageal GISTs involve the lower third of the oesophagus or gastro-oesophageal junction. They typically resemble gastric GISTs and usually show spindle cell morphology (Greenson, 2003). The majority of oesophageal GISTs are malignant.

Colonic GISTs and ano-rectal GISTs appear to be morphologically more similar to intestinal than gastric GISTs (Greenson, 2003). The majority are malignant with pleomorphic or overtly malignant spindle cell morphology.

Fig. 3. GIST with a myxoid stroma (A), stromal haemorrhage (B), Skenoid fibres (C) and PAS positive skenoid fibres (D).

## **8. Gastrointestinal autonomic nerve tumours**

182 Soft Tissue Tumors

The stroma in GISTs may be myxoid or it may be hyalinised (Figure 3A) or calcified. Delicate thin walled blood vessels may be prominent and may be associated with stromal

Gastric GISTs have spindle cell morphology in 50% of cases, while 30% are epithelioid and

Small intestinal GISTs are more often spindled and may show extracellular bright eosinophilic collagen globules termed "skenoid fibres" (Figure 3C). These structures are periodic acid-Schiff (PAS) positive (Figure 3D). Small bowel tumours with an epithelioid

Studies on oesophageal, colonic, ano-rectal and extra-gastrointestinal GISTs are sparse. Oesophageal GISTs involve the lower third of the oesophagus or gastro-oesophageal junction. They typically resemble gastric GISTs and usually show spindle cell morphology

Colonic GISTs and ano-rectal GISTs appear to be morphologically more similar to intestinal than gastric GISTs (Greenson, 2003). The majority are malignant with pleomorphic or

Fig. 3. GIST with a myxoid stroma (A), stromal haemorrhage (B), Skenoid fibres (C) and PAS

haemorrhage (Figure 3B). Necrosis may be present. Lymphocytes can be seen.

morphology are usually associated with an aggressive behaviour.

(Greenson, 2003). The majority of oesophageal GISTs are malignant.

20% are mixed (Miettinen et al., 2005).

overtly malignant spindle cell morphology.

positive skenoid fibres (D).

GANTs were originally designated "plexoma" and "plexosarcoma" based on ultrastructural resemblance to cells of autonomic nervous system. GANTs are uncommon tumours which can occasionally develop in the context of von Recklinghausen's disease (Lespi & Drut, 1997) and Carney's triad (Segal et al., 1994). Familial multiple GANTs have been described in an association with intestinal neuronal dysplasia (O'Brien et al., 1999).

The characteristic ultrastructural features include complex interdigitating cell processes with bulbulous synaptic structures, dense core neurosecretory granules, rudimentary cell junctions and intermediate filaments.

Although originally believed to be a distinct tumour, recent evidence supports the concept that GANTs represent a phenotyptic variant of GISTs (Segal et al., 1994). These tumours tend to be KIT positive and a most have gain of function mutation in the juxtamembrane domain of *c-kit* (Lee et al., 2001).

## **9. Immunohistochemical features**

The overwhelming majority of GISTs express KIT protein (detected as CD117). The results of KIT immunostaining depend on several technical factors including fixation, tissue preparation, variations in antibody clones in terms of specificity and sensitivity, antibody dilutions and staining techniques. This may account in part for the reported immunophenotypic heterogeneity in GISTs. It has been emphasised that CD117 should be performed without epitope retrieval (Fletcher & Fletcher, 2002).

The monoclonal antibodies currently available react inconsistently in formalin fixed paraffin embedded tissue and identify only a minority of GISTs (Miettinen et al., 2002b).

Given the potential clinical importance of CD117 immunostaining, optimisation of the staining techniques and reproducibility are critical.

The pattern of staining is variable (Figure 4). Diffuse strong pancytoplasmic staining is the predominant pattern. Membranous staining and dot-like "golgi zone pattern" staining can be identified. It has been suggested that different staining patterns correlate with different types of *c-kit* mutations (Fletcher et al., 2002a). Stromal mast cells and ICC are useful internal positive controls to supplement the normal positive and negative controls.

Fig. 4. Pattern of CD117 immunostaining. GIST showing membranous and cytoplasmic staining (A) and golgi zone-like staining (B).

Gastrointestinal Stromal Tumours:

**10. Differential diagnosis** 

**10.1 Smooth muscle tumours** 

(Miettinen et al., 2001).

However, experience with this marker is limited.

The differential diagnosis of GISTs is wide and includes the following:

muscle tumours are positive for CD34 (Fletcher et al., 2002a).

whereas GISTs are negative for hormonal receptors.

to uterine leiomyoma (Dow et al., 2006).

positive and CD117 negative.

**10.2 Schwannoma** 

negative for CD117.

A Contemporary Review on Pathogenesis, Morphology and Prognosis 185

reported in 98% of GISTs, including several CD117- negative tumours (Motegi et al., 2005).

Intramural leiomyomas are most common in the oesophagus, and in fact, leiomyomas in this location outnumber GISTs by 3:1 (Dow et al., 2006). Oesophageal leiomyomas arise typically in young men, usually in the lower third of the oesophagus. Intramural leiomyomas are rare in the stomach and small intestine, but are common in the colon (Miettinen et al., 2001). Muscularis mucosae leiomyomas are usually small polypoid lesions found incidentally at colonoscopy and are most often found in the colon and rectum

Morphologically, leiomyomas are generally less cellular than GISTs and are composed of bland spindle cells with eosinophilic cytoplasm and cigar shaped nuclei. Rare cases may show nuclear atypia without mitotic activity. Calcifications may be seen. The cells are positive for desmin and actin and negative for CD117. Approximately 10-15% of smooth

Pelvic uterine leiomyomas may become attached to the colon and therefore may mimic GISTs. These tumours resemble uteric leiomyomas morphologically and are positive for actin and desmin. The tumours are also oestrogen and progesterone receptors positive,

Leiomyomatosis peritonealis disseminate represents numerous small (2-3mm), smooth muscle nodules on the peritoneum (Tavassoli & Norris, 1982). The nodules are composed of smooth muscle cells with no atypia and low mitotic activity, usually less than 2/10 high power fields (HPFs) (Dow et al., 2006). The cells have similar immunohistochemical features

Leiomyosarcomas of the gastrointestinal tract are rare. They usually occur in older adults with a female predilection and are most common in the colon (Dow et al., 2006). The tumour cells show nuclear pleomorphism, mitotic activity and necrosis. They are actin and desmin

This is a rare mesenchymal tumours of the gastrointestinal tract. It occurs most frequently in the stomach with a peak incidence in 6th and 7th decades. The tumour typically involves the submucosa and the muscularis propria. Histologically, it appears as a sharply demarcated but unencapsulated lesion often surrounded by a lymphoid cuff. The tumour is usually small in size (< 5cm) and is composed of spindle cells with wavy nuclei and occasional intranuclear inclusions. Mitoses are rare (< 5/50 HPFs). The cells are positive for S100 protein. Antoni B areas may express CD34 (Fletcher et al., 2002a), however the cells are

Gastrointestinal schwannoma lack *NF2* gene alterations found in many soft tissue schwannomas. In addition, they frequently exhibit glial fibrillary acidic protein (GFAP) which is not a feature in soft tissue sarcomas. On this basis, it has been suggested that

Immunoreactivity may also be patchy, and thus false negative staining can be encountered in small biopsy specimens.

Immunohistochemical detection of KIT does not necessarily imply *c-kit* activation. Indeed CD117 is expressed by other tumour types such as melanoma and soft tissue sarcomas including dermatofibrosarcoma protuberans, synovial sarcoma and angiosarcoma (Sabah et al., 2003). The CD117 immunoreactivity should therefore, be interpreted in the context of morphology and clinical setting.

Approximately 5% of GISTs are KIT negative (Debiec-Rychter et al., 2004b; Medeiros et al., 2004). In these exceptional circumstances, KIT-negative mesenchymal lesions in the gastrointestinal tract with typical morphological features of GISTs may be referred to as "A stromal neoplasm most consistent with GIST". Such rare scenarios include GISTs that are either immunohistochemically inert for technical reasons, the subject of sampling error (biopsy of tumour with only focal KIT staining), the product of clonal evolution with emergence of KIT negative clone following imatinib therapy, or a rare example of a true GIST lacking KIT expression (Fletcher et al., 2002a; Parfitt et al., 2006). In such cases, pathologists should consider consultation with those experienced in dealing with large numbers of GISTs, as well as mutational analysis to look for mutations in *c-kit* and, if negative, *PDGFRA* (Corless et al., 2004; Medeiros et al., 2004).

DOG1 expression is found to be specific and sensitive for GISTs including KIT negative tumours (Espinosa et al., 2008; West et al., 2004). It has been reported in over 95% of cases.

CD34 is a transmembrane glycoprotein present on human haematopoietic progenitor cells and vascular endothelium. CD34 is detectable in approximately 60-70%. The oesophageal and rectal GISTs have the highest frequency of CD34 positivity, whereas small intestinal tumours have the lowest percentage of CD34 positivity (Miettinen et al., 2000b).

Muscle markers such as actin, calponin and h-caldesmon are positive in approximately 30% of cases (Miettinen et al., 2000b). α-smooth muscle actin (SMA) expression is often reciprocal with CD34 expression: the SMA positive tumours are often CD34 negative and vice versa. Some tumours may show mosaic pastern with actin positive and CD34 negative areas and vice versa (Miettinen et al., 2000b). Desmin positive immunostaining is uncommon (2%) (Fletcher et al., 2002a) and is often limited to scattered tumour cells. Prominent staining is more common in epithelioid tumours.

Positive staining for S100 protein occurs in 5-10% of GISTs, especially in small bowel tumours (Fletcher et al., 2002a). These tumours are usually negative for other neural markers including neurofilament and glial fibrillary protein.

Focal positive staining for cytokeratin markers can be seen especially in malignant epithelioid GISTs.

Data on immunohistochemical staining for PDGFRA protein are scant. Rossi et al (Rossi et al., 2005) evaluated the role of PDGFR immunohistochemistry in the differential diagnosis of KIT-negative GISTs. They reported positive expression of PDGFR, in KIT-negative GISTs, while KIT-positive GISTs, smooth muscle tumours, schwannomas and solitary fibrous tumours did not; however, 27% of desmoid tumours were also positive for PDGFRA. PDGFRA immunohistochemistry has not been standardised to be of practical diagnostic value in GISTs and many available antibodies do not appear reliable on paraffin-embedded material.

Protein kinase C theta (PKCθ) is a downstream effector in the KIT signalling pathway and has been suggested as an immunohistochemical marker for GISTs with a high specificity and sensitivity (Blay et al., 2004; Duensing et al., 2004). The expression of PKCθ has been reported in 98% of GISTs, including several CD117- negative tumours (Motegi et al., 2005). However, experience with this marker is limited.

## **10. Differential diagnosis**

184 Soft Tissue Tumors

Immunoreactivity may also be patchy, and thus false negative staining can be encountered

Immunohistochemical detection of KIT does not necessarily imply *c-kit* activation. Indeed CD117 is expressed by other tumour types such as melanoma and soft tissue sarcomas including dermatofibrosarcoma protuberans, synovial sarcoma and angiosarcoma (Sabah et al., 2003). The CD117 immunoreactivity should therefore, be interpreted in the context of

Approximately 5% of GISTs are KIT negative (Debiec-Rychter et al., 2004b; Medeiros et al., 2004). In these exceptional circumstances, KIT-negative mesenchymal lesions in the gastrointestinal tract with typical morphological features of GISTs may be referred to as "A stromal neoplasm most consistent with GIST". Such rare scenarios include GISTs that are either immunohistochemically inert for technical reasons, the subject of sampling error (biopsy of tumour with only focal KIT staining), the product of clonal evolution with emergence of KIT negative clone following imatinib therapy, or a rare example of a true GIST lacking KIT expression (Fletcher et al., 2002a; Parfitt et al., 2006). In such cases, pathologists should consider consultation with those experienced in dealing with large numbers of GISTs, as well as mutational analysis to look for mutations in *c-kit* and, if

DOG1 expression is found to be specific and sensitive for GISTs including KIT negative tumours (Espinosa et al., 2008; West et al., 2004). It has been reported in over 95% of cases. CD34 is a transmembrane glycoprotein present on human haematopoietic progenitor cells and vascular endothelium. CD34 is detectable in approximately 60-70%. The oesophageal and rectal GISTs have the highest frequency of CD34 positivity, whereas small intestinal

Muscle markers such as actin, calponin and h-caldesmon are positive in approximately 30% of cases (Miettinen et al., 2000b). α-smooth muscle actin (SMA) expression is often reciprocal with CD34 expression: the SMA positive tumours are often CD34 negative and vice versa. Some tumours may show mosaic pastern with actin positive and CD34 negative areas and vice versa (Miettinen et al., 2000b). Desmin positive immunostaining is uncommon (2%) (Fletcher et al., 2002a) and is often limited to scattered tumour cells. Prominent staining is

Positive staining for S100 protein occurs in 5-10% of GISTs, especially in small bowel tumours (Fletcher et al., 2002a). These tumours are usually negative for other neural

Focal positive staining for cytokeratin markers can be seen especially in malignant

Data on immunohistochemical staining for PDGFRA protein are scant. Rossi et al (Rossi et al., 2005) evaluated the role of PDGFR immunohistochemistry in the differential diagnosis of KIT-negative GISTs. They reported positive expression of PDGFR, in KIT-negative GISTs, while KIT-positive GISTs, smooth muscle tumours, schwannomas and solitary fibrous tumours did not; however, 27% of desmoid tumours were also positive for PDGFRA. PDGFRA immunohistochemistry has not been standardised to be of practical diagnostic value in GISTs and many available antibodies do not appear reliable on paraffin-embedded

Protein kinase C theta (PKCθ) is a downstream effector in the KIT signalling pathway and has been suggested as an immunohistochemical marker for GISTs with a high specificity and sensitivity (Blay et al., 2004; Duensing et al., 2004). The expression of PKCθ has been

tumours have the lowest percentage of CD34 positivity (Miettinen et al., 2000b).

in small biopsy specimens.

morphology and clinical setting.

more common in epithelioid tumours.

epithelioid GISTs.

material.

negative, *PDGFRA* (Corless et al., 2004; Medeiros et al., 2004).

markers including neurofilament and glial fibrillary protein.

The differential diagnosis of GISTs is wide and includes the following:

## **10.1 Smooth muscle tumours**

Intramural leiomyomas are most common in the oesophagus, and in fact, leiomyomas in this location outnumber GISTs by 3:1 (Dow et al., 2006). Oesophageal leiomyomas arise typically in young men, usually in the lower third of the oesophagus. Intramural leiomyomas are rare in the stomach and small intestine, but are common in the colon (Miettinen et al., 2001). Muscularis mucosae leiomyomas are usually small polypoid lesions found incidentally at colonoscopy and are most often found in the colon and rectum (Miettinen et al., 2001).

Morphologically, leiomyomas are generally less cellular than GISTs and are composed of bland spindle cells with eosinophilic cytoplasm and cigar shaped nuclei. Rare cases may show nuclear atypia without mitotic activity. Calcifications may be seen. The cells are positive for desmin and actin and negative for CD117. Approximately 10-15% of smooth muscle tumours are positive for CD34 (Fletcher et al., 2002a).

Pelvic uterine leiomyomas may become attached to the colon and therefore may mimic GISTs. These tumours resemble uteric leiomyomas morphologically and are positive for actin and desmin. The tumours are also oestrogen and progesterone receptors positive, whereas GISTs are negative for hormonal receptors.

Leiomyomatosis peritonealis disseminate represents numerous small (2-3mm), smooth muscle nodules on the peritoneum (Tavassoli & Norris, 1982). The nodules are composed of smooth muscle cells with no atypia and low mitotic activity, usually less than 2/10 high power fields (HPFs) (Dow et al., 2006). The cells have similar immunohistochemical features to uterine leiomyoma (Dow et al., 2006).

Leiomyosarcomas of the gastrointestinal tract are rare. They usually occur in older adults with a female predilection and are most common in the colon (Dow et al., 2006). The tumour cells show nuclear pleomorphism, mitotic activity and necrosis. They are actin and desmin positive and CD117 negative.

### **10.2 Schwannoma**

This is a rare mesenchymal tumours of the gastrointestinal tract. It occurs most frequently in the stomach with a peak incidence in 6th and 7th decades. The tumour typically involves the submucosa and the muscularis propria. Histologically, it appears as a sharply demarcated but unencapsulated lesion often surrounded by a lymphoid cuff. The tumour is usually small in size (< 5cm) and is composed of spindle cells with wavy nuclei and occasional intranuclear inclusions. Mitoses are rare (< 5/50 HPFs). The cells are positive for S100 protein. Antoni B areas may express CD34 (Fletcher et al., 2002a), however the cells are negative for CD117.

Gastrointestinal schwannoma lack *NF2* gene alterations found in many soft tissue schwannomas. In addition, they frequently exhibit glial fibrillary acidic protein (GFAP) which is not a feature in soft tissue sarcomas. On this basis, it has been suggested that

Gastrointestinal Stromal Tumours:

**10.6 Solitary fibrous tumour** 

(Gengler & Guillou, 2006).

CD34 and CD117.

**10.8 Glomus tumours** 

**10.9 Miscellaneous lesions** 

HMB45 and Melan-A.

**10.7 Sclerosing mesenteritis** 

seen in 30% of cases (Miettinen et al., 2002c).

carcinoma, melanoma and clear cell sarcoma.

translocation with EWS-ATF1 gene fusions.

and negative for CD117 and CD34.

occur anywhere along the midline of the retroperitoneum.

cases the primary site is an intra-abdominal neoplasm.

A Contemporary Review on Pathogenesis, Morphology and Prognosis 187

Solitary fibrous tumour may involve the peritoneal cavity and adhere to the bowel. It is characterised by a spindle cell proliferation admixed with collagen and "staghorn" blood

Predicting the clinical behaviour of solitary fibrous tumour is notoriously difficult, but large size, infiltrative margins, high cellularity, nuclear pleomorphism, tumour necrosis and high mitotic count (> 4/10 HPFs) are all associated with an increased risk of malignant behaviour

This tumour-like lesion affects the small bowel mesentery. It consists of fibrous bands infiltrating and encasing fat lobules with fat necrosis. Chronic inflammatory cells including lymphocytes, plasma cells and eosinophils are usually present. The cells are negative for

These tumours rarely occur in the gastrointestinal tract. They are found almost exclusively in the stomach and mainly in women (Dow et al., 2006). They are usually benign and similar to peripheral glomus tumours. They are made up of round uniform cells arranged around prominent dilated haemangiopericytoma-like vessels. The cells are positive for smooth muscle actin and negative for desmin, S100 protein and CD117. CD34 positive staining is

GISTs with epithelioid morphology may be mistaken for paraganglioma, metastatic

Paragangliomas arise outside the adrenal gland in approximately 10% of the cases. They

Metastatic carcinoma is the most common type of solid tumour of the mesentry and in most

Malignant melanoma has a tendency to metastasise to the gastrointestinal tract. They are CD117 positive but can be distinguished from GISTs by the expression of S100 protein,

Clear cell sarcoma may rarely involve the gastrointestinal tract. The tumour cells are diffusely positive for S100 protein, but unlike peripheral clear cell sarcoma, they are negative for HMB45 and Melan-A. They are characterised by the presence of t(12;22)

Mesothelioma with a sarcomatoid morphology may also mimic GIST if it involves the bowel. Mesothelioma cells are positive for calretinin and negative for CD34 and CD117. Follicular dendritic cells sarcoma affects the spleen, but may extend into the adjacent structures. The tumour is composed of sheets and whorls of cells with ovoid nuclei. The cells are intimately associated with small lymphocytes and are positive for CD21 and CD35

Dedifferentiated retroperitoneal liposarcoma may be attached to the bowel wall and sometimes simulate GISTs. Thorough sampling usually reveals a lipomatous component.

vessels. The tumour cells are positive for CD34 but negative for CD117.

gastrointestinal schwannomas may represent a distinctive group of peripheral nerve sheath tumours (Lasota et al., 2003b).

#### **10.3 Intra-abdominal fibromatosis**

These are locally aggressive lesions but they usually do not metastasise. They occur either sporadically or in association with Gardner's syndrome, typically in young and middle-ages adults. Intra-abdominal fibromatoses are the most common primary tumours of the mesentery. The most common site is the mesentery of the small bowel, but some originate from the ileocolic mesentery, gastrocolic ligament or omentum. They may also occur in the reteroperitoneum and may involve the bowel wall. Most patients present with an asymptomatic mass, but some present with gastrointestinal bleeding or an acute abdomen secondary to bowel perforation.

These lesions are usually large in size, more than 10cm in diameter. Although grossly well circumscribed, they tend to infiltrate the surrounding tissue. Histologically, they are composed of spindle cell proliferation arranged in parallel with evenly spaced blood vessels. The stroma is typically collagenous with keloid-like fibres and thin-walled blood vessels. Mitotic figures can be identified.

CD117 has been reported to be positive depending on the antibody used (Miettinen, 2001; Yantiss et al., 2000). However, studies have suggested that under optimum technical conditions, intra-abdominal fibromatosis are CD117- negative tumours (Lucas et al., 2003). Nuclear immunoreactivity for β-catenin in these tumours has been reported to be useful in distinguishing these tumours from GISTs (Montgomery et al., 2002). CD34 is negative.

#### **10.4 Inflammatory myofibroblastic tumour**

Inflammatory myofibroblastic tumour known as "inflammatory psuedo tumour". The lesion often occurs in children but may be present in adults. It is commonly located on the peritoneal surface, but may involve the omentum, mesentery, stomach or intestinal wall. Patients with inflammatory myofibroblastic tumours present with abdominal pain and abdominal mass which may be associated with obstruction. Some patients present with fever, night sweats, malaise and weight loss. Whilst some of these lesions are felt to be benign reactions to infectious processes, others have been shown to be clonal in origin (Cook et al., 2001). Inflammatory myofibroblastic tumours are lobular or multinodular.

Histologically, they are characterised by spindled or stellate shaped cellular proliferation admixed with lymphocytes and plasma cells with streaks of fibrosis. The cells are positive for desmin and actin and negative for CD117 and CD34. A high proportion of these lesions are also positive for anaplastic lymphoma kinase (ALK1) (Cook et al., 2001).

#### **10.5 Inflammatory fibroid polyp**

This is a tumour-like lesion that occurs in adults and most often encountered in the small intestine, especially ileum and the stomach. The peak incidence is in the 6th to 7th decade of life. The lesion arises in the submucosa and is usually well circumscribed. It is composed of spindle cell proliferation admixed with granulation tissue-like blood vessels in a loose oedematous stroma. The cells may show concentric arrangement around the blood vessels, the so called "onion-skin pattern". Mixed inflammatory cells are present, comprising plasma cells, lymphocytes and mast cells. Eosinophils are usually prominent. The majority of these lesions are positive for CD34 but are negative for CD1117.

#### **10.6 Solitary fibrous tumour**

186 Soft Tissue Tumors

gastrointestinal schwannomas may represent a distinctive group of peripheral nerve sheath

These are locally aggressive lesions but they usually do not metastasise. They occur either sporadically or in association with Gardner's syndrome, typically in young and middle-ages adults. Intra-abdominal fibromatoses are the most common primary tumours of the mesentery. The most common site is the mesentery of the small bowel, but some originate from the ileocolic mesentery, gastrocolic ligament or omentum. They may also occur in the reteroperitoneum and may involve the bowel wall. Most patients present with an asymptomatic mass, but some present with gastrointestinal bleeding or an acute abdomen

These lesions are usually large in size, more than 10cm in diameter. Although grossly well circumscribed, they tend to infiltrate the surrounding tissue. Histologically, they are composed of spindle cell proliferation arranged in parallel with evenly spaced blood vessels. The stroma is typically collagenous with keloid-like fibres and thin-walled blood vessels.

CD117 has been reported to be positive depending on the antibody used (Miettinen, 2001; Yantiss et al., 2000). However, studies have suggested that under optimum technical conditions, intra-abdominal fibromatosis are CD117- negative tumours (Lucas et al., 2003). Nuclear immunoreactivity for β-catenin in these tumours has been reported to be useful in distinguishing these tumours from GISTs (Montgomery et al., 2002). CD34 is negative.

Inflammatory myofibroblastic tumour known as "inflammatory psuedo tumour". The lesion often occurs in children but may be present in adults. It is commonly located on the peritoneal surface, but may involve the omentum, mesentery, stomach or intestinal wall. Patients with inflammatory myofibroblastic tumours present with abdominal pain and abdominal mass which may be associated with obstruction. Some patients present with fever, night sweats, malaise and weight loss. Whilst some of these lesions are felt to be benign reactions to infectious processes, others have been shown to be clonal in origin (Cook

Histologically, they are characterised by spindled or stellate shaped cellular proliferation admixed with lymphocytes and plasma cells with streaks of fibrosis. The cells are positive for desmin and actin and negative for CD117 and CD34. A high proportion of these lesions

This is a tumour-like lesion that occurs in adults and most often encountered in the small intestine, especially ileum and the stomach. The peak incidence is in the 6th to 7th decade of life. The lesion arises in the submucosa and is usually well circumscribed. It is composed of spindle cell proliferation admixed with granulation tissue-like blood vessels in a loose oedematous stroma. The cells may show concentric arrangement around the blood vessels, the so called "onion-skin pattern". Mixed inflammatory cells are present, comprising plasma cells, lymphocytes and mast cells. Eosinophils are usually prominent. The majority of these

et al., 2001). Inflammatory myofibroblastic tumours are lobular or multinodular.

are also positive for anaplastic lymphoma kinase (ALK1) (Cook et al., 2001).

lesions are positive for CD34 but are negative for CD1117.

tumours (Lasota et al., 2003b).

**10.3 Intra-abdominal fibromatosis** 

secondary to bowel perforation.

Mitotic figures can be identified.

**10.5 Inflammatory fibroid polyp** 

**10.4 Inflammatory myofibroblastic tumour** 

Solitary fibrous tumour may involve the peritoneal cavity and adhere to the bowel. It is characterised by a spindle cell proliferation admixed with collagen and "staghorn" blood vessels. The tumour cells are positive for CD34 but negative for CD117.

Predicting the clinical behaviour of solitary fibrous tumour is notoriously difficult, but large size, infiltrative margins, high cellularity, nuclear pleomorphism, tumour necrosis and high mitotic count (> 4/10 HPFs) are all associated with an increased risk of malignant behaviour (Gengler & Guillou, 2006).

## **10.7 Sclerosing mesenteritis**

This tumour-like lesion affects the small bowel mesentery. It consists of fibrous bands infiltrating and encasing fat lobules with fat necrosis. Chronic inflammatory cells including lymphocytes, plasma cells and eosinophils are usually present. The cells are negative for CD34 and CD117.

## **10.8 Glomus tumours**

These tumours rarely occur in the gastrointestinal tract. They are found almost exclusively in the stomach and mainly in women (Dow et al., 2006). They are usually benign and similar to peripheral glomus tumours. They are made up of round uniform cells arranged around prominent dilated haemangiopericytoma-like vessels. The cells are positive for smooth muscle actin and negative for desmin, S100 protein and CD117. CD34 positive staining is seen in 30% of cases (Miettinen et al., 2002c).

## **10.9 Miscellaneous lesions**

GISTs with epithelioid morphology may be mistaken for paraganglioma, metastatic carcinoma, melanoma and clear cell sarcoma.

Paragangliomas arise outside the adrenal gland in approximately 10% of the cases. They occur anywhere along the midline of the retroperitoneum.

Metastatic carcinoma is the most common type of solid tumour of the mesentry and in most cases the primary site is an intra-abdominal neoplasm.

Malignant melanoma has a tendency to metastasise to the gastrointestinal tract. They are CD117 positive but can be distinguished from GISTs by the expression of S100 protein, HMB45 and Melan-A.

Clear cell sarcoma may rarely involve the gastrointestinal tract. The tumour cells are diffusely positive for S100 protein, but unlike peripheral clear cell sarcoma, they are negative for HMB45 and Melan-A. They are characterised by the presence of t(12;22) translocation with EWS-ATF1 gene fusions.

Mesothelioma with a sarcomatoid morphology may also mimic GIST if it involves the bowel. Mesothelioma cells are positive for calretinin and negative for CD34 and CD117.

Follicular dendritic cells sarcoma affects the spleen, but may extend into the adjacent structures. The tumour is composed of sheets and whorls of cells with ovoid nuclei. The cells are intimately associated with small lymphocytes and are positive for CD21 and CD35 and negative for CD117 and CD34.

Dedifferentiated retroperitoneal liposarcoma may be attached to the bowel wall and sometimes simulate GISTs. Thorough sampling usually reveals a lipomatous component.

Gastrointestinal Stromal Tumours:

**Uncertain (low malignant potential)** 

**GIST groups** 

**GIST categories Criteria for diagnosis** 

5/50 HPFs

HPFs

HPFs

HPFs

malignancy (Miettinen et al., 2002a).

**Tumour size (cm)** 

**4** ≤ 2 > 5

(Miettinen & Lasota, 2006b).

al., 2006; Miettinen & Lasota, 2006b) (Table 3).

more than 5/50 HPFs

more than 5/50 HPFs

**Mitotic count (per 50 HPFs)**

**<sup>2</sup>**>2 ≤5 ≤5 Gastric: low (1.9%)

**3a** >5 ≤10 ≤5 Gastric: low (3.6%)

**6a** >5 ≤10 > 5 Gastric: high (55%)

**6b** > 10 > 5 Gastric: high (86%)

**1** ≤ 2 ≤5 Gastric: very low if any (0%)

**3b** > 10 ≤5 Gastric: intermediate (12%)

**<sup>5</sup>**>2 ≤5 > 5 Gastric: intermediate (16%)

A Contemporary Review on Pathogenesis, Morphology and Prognosis 189

**Probably benign Intestinal tumours**: Maximum diameter ≤ 2 cm *and* no more than

**Probably malignant Intestinal tumours**: Maximum diameter > 5 cm *or* more than 5/50

Table 2. Tumour size, mitotic rate and tumour site as guides to the evaluation of GIST

Recent large series have evaluated the behaviour of large number of gastric and small intestinal GISTs. Because the data antedates imatinib application, it gives an insight into the natural history of GISTs. Based on the tumour size, mitotic count and the anatomic location of the tumour, GISTs are classified into different groups (Miettinen et al., 2005; Miettinen et

**potential** 

predict)

Table 3. Risk assessment of GISTs based on tumour size, mitotic count and tumour site

**Gastric tumours**: Maximum diameter ≤ 5 cm *and* no more than 5/50

**Gastric tumours**: Maximum diameter > 10 cm *or* more than 5/50

**Intestinal tumours**: Maximum diameter >2 cm but ≤ 5 cm *and* no

**Gastric tumours**: Maximum diameter > 5 cm and ≤ 10 cm *and* no

**Risk of progressive disease and malignant** 

Small intestinal: very low if any (0%)

Small intestinal: intermediate (24%)

Gastric: low (0% but too few cases to predict) Small intestinal: high (50% but too few cases to

Small intestinal: low (4.3%)

Small intestinal: high (52%)

Small intestinal: high (73%)

Small intestinal: high (85%)

Small intestinal: high (90%)

Angiosarcoma can simulate GIST and can be positive for CD117, but the specific histologic and immunohistochemical features allow for the differential diagnosis from GIST.

Synovial sarcoma may rarely occur in the gastrointestinal tract, abdominal wall and retropeitoneum. Some immunohistochemical studies have shown KIT expression in synovial sarcomas (Sabah et al., 2003; Tamborini et al., 2001). However, synovial sarcoma exhibits (X;18) (p11.2;q11.2) translocation.

## **11. Prognostic factors**

Several clinicopathological and cytogenetic features have prognostic relevance:

## **11.1 Clinicopathologic factors**

#### **11.1.1 Tumour stage at presentation**

The presence of peritoneal or liver metastases at presentation is an adverse prognostic factor and is associated with a shorter survival (Dematteo et al., 2000). Invasion of adjacent organs also correlates with a poor outcome.

## **11.1.2 Tumour size, site and mitotic activity**

The subset of GISTs that has a high likelihood of malignant behaviour is generally identified by increased tumour size and mitotic activity in the context of tumour location (Miettinen et al., 2002a; Miettinen et al., 2005; Miettinen et al., 2006; Miettinen & Lasota, 2006b). The size of the tumour should be measured along the greatest axis of the tumour. The mitotic count is most accurately expressed as the number of mitoses per 50 HPFs and should be performed on areas with highest mitotic activity. This requires adequate sampling of the tumour.

Based on the size of the tumour and mitotic count, GISTs can be classified into very low risk, low risk, intermediate risk and high risk (Fletcher et al., 2002a; Fletcher et al., 2002b) (Table 1).


Table 1. Tumour size and mitotic rate as guides to the evaluation of GIST malignancy (Fletcher et al., 2002b).

In recent years, it has become clear that GISTs require site evaluation because of differing behaviour (Emory et al., 1999; Miettinen et al., 2002a). It has been suggested that the site of the tumour is a prognostic factor independent of the tumour size and mitotic count (Emory et al., 1999) with small bowel tumours having the worst prognosis. This provided a rationale for the proposed site specific evaluation of GIST. In this classification, GIST is classified according to the site, size and mitotic count into three categories: benign, malignant and uncertain or low malignant potential (Miettinen et al., 2002a) (Table 2).

Angiosarcoma can simulate GIST and can be positive for CD117, but the specific histologic

Synovial sarcoma may rarely occur in the gastrointestinal tract, abdominal wall and retropeitoneum. Some immunohistochemical studies have shown KIT expression in synovial sarcomas (Sabah et al., 2003; Tamborini et al., 2001). However, synovial sarcoma

The presence of peritoneal or liver metastases at presentation is an adverse prognostic factor and is associated with a shorter survival (Dematteo et al., 2000). Invasion of adjacent organs

The subset of GISTs that has a high likelihood of malignant behaviour is generally identified by increased tumour size and mitotic activity in the context of tumour location (Miettinen et al., 2002a; Miettinen et al., 2005; Miettinen et al., 2006; Miettinen & Lasota, 2006b). The size of the tumour should be measured along the greatest axis of the tumour. The mitotic count is most accurately expressed as the number of mitoses per 50 HPFs and should be performed on areas with highest mitotic activity. This requires adequate sampling of the

Based on the size of the tumour and mitotic count, GISTs can be classified into very low risk, low risk, intermediate risk and high risk (Fletcher et al., 2002a; Fletcher et al., 2002b) (Table 1).

> 6-10 <5

> 5 Any mitotic rate > 10

**GIST categories Tumour size (cm) Mitotic count (per 50 HPFs)** 

Table 1. Tumour size and mitotic rate as guides to the evaluation of GIST malignancy

In recent years, it has become clear that GISTs require site evaluation because of differing behaviour (Emory et al., 1999; Miettinen et al., 2002a). It has been suggested that the site of the tumour is a prognostic factor independent of the tumour size and mitotic count (Emory et al., 1999) with small bowel tumours having the worst prognosis. This provided a rationale for the proposed site specific evaluation of GIST. In this classification, GIST is classified according to the site, size and mitotic count into three categories: benign, malignant and

**Very low risk** < 2 <5 **Low risk** 2-5 <5

5-10

> 5 > 10 Any size

uncertain or low malignant potential (Miettinen et al., 2002a) (Table 2).

and immunohistochemical features allow for the differential diagnosis from GIST.

Several clinicopathological and cytogenetic features have prognostic relevance:

exhibits (X;18) (p11.2;q11.2) translocation.

**11. Prognostic factors** 

tumour.

**High risk** 

(Fletcher et al., 2002b).

**11.1 Clinicopathologic factors 11.1.1 Tumour stage at presentation** 

also correlates with a poor outcome.

**Intermediate risk** <5

**11.1.2 Tumour size, site and mitotic activity** 


Table 2. Tumour size, mitotic rate and tumour site as guides to the evaluation of GIST malignancy (Miettinen et al., 2002a).

Recent large series have evaluated the behaviour of large number of gastric and small intestinal GISTs. Because the data antedates imatinib application, it gives an insight into the natural history of GISTs. Based on the tumour size, mitotic count and the anatomic location of the tumour, GISTs are classified into different groups (Miettinen et al., 2005; Miettinen et al., 2006; Miettinen & Lasota, 2006b) (Table 3).


Table 3. Risk assessment of GISTs based on tumour size, mitotic count and tumour site (Miettinen & Lasota, 2006b).

Gastrointestinal Stromal Tumours:

(Goldblum & Appelman, 1995).

**11.1.7 Nuclear pleomorphism** 

**11.1.8 Immunohistochemical markers** 

and tumour progression of many tumours.

GISTs

**11.1.6 Cellularity** 

(Wong et al., 2003).

Steigen et al., 2008).

2003; Sabah et al., 2006).

genetic studies.

A Contemporary Review on Pathogenesis, Morphology and Prognosis 191

mucosal ulceration has no prognostic significance as it is found in benign and malignant

Low cellularity has emerged as a favourable prognostic feature according to some studies

Marked nuclear pleomorphism in a spindle cell tumour suggests a malignant behavior, on the other hand, scattered bizarre multinucleated cells are characteristic of benign lesions.

Proliferation markers (Ki-67, MIB-1 and proliferating cell nuclear antigen (PCNA)) may aid in tumour evaluation. It has been reported that tumours with more than 10% of nuclei for Ki-67 analogue are associated with metastases and poor survival rate (Amin et al., 1993; Panizo-Santos et al., 2000; Reith et al., 2000; Rudolph et al., 1998; Wang et al., 2002). One study has reported that MIB-1 index was not superior to mitotic count as a prognostic factor

Alterations affecting certain cell cycle regulators have been implicated in the pathogenesis

The tumour suppressor gene *p16INK4* encodes a nuclear protein that belongs to the INK4A family of cyclin dependent kinase inhibitors and blocks cell cycle progression at the G1-S transition (Serrano et al., 1993). It has been reported that loss of p16 immunostaining is associated with high risk GISTs (Haller et al., 2005; Liang et al., 2007; Ricci et al., 2004; Sabah et al., 2004b; Sabah et al., 2006; Schneider-Stock et al., 2003; Schneider-Stock et al., 2005;

Another gene*, p27KIP1* is also a cyclin dependent kinase inhibitor that belongs to the CIP/ KIP family. An inverse correlation between p27KIP1 protein expression and the degree of malignancy has been observed. Low p27KIP1 expression seems to be associated with aggressive clinical behaviour in GISTs (Gelen et al., 2003; Nemoto et al., 2006; Pruneri et al.,

E2F1 is a transcription factor. Phosphorylation of the Rb protein results in the release of E2F proteins, that are necessary for progression into S phase. Expression of E2F1 has been

Finally, the expression of p53, a transcription factor and a cell cycle regulator, has been extensively investigated in human malignancies including GISTs. Most studies have suggested that p53 expression correlates with histologically malignant GISTs (Al Bozom, 2001; Cunningham et al., 2001; Feakins, 2005; Gumurdulu et al., 2007; Haller et al., 2005; Hata et al., 2006; Hillemanns et al., 1998; Ryu et al., 2007; Sabah et al., 2006; Wang & Kou,

Prediction of clinical outcome on the basis of morphology alone is not always reliable. Other new and promising parameters that may aid prognostic evaluation may emerge from

reported to be an adverse prognostic factor (Haller et al., 2005; Sabah et al., 2006).

2007; Wang et al., 2002; Wong et al., 2003; Yalcinkaya et al., 2007).

**11.2 Cytogenetic markers as prognostic factors** 

A scheme proposed under the aegis of the National Institutes of Health (NIH) defined the risk of aggressive behaviour using the twin criteria of tumour size and mitotic activity count irrespective of tumour location. A significant body of opinion holds that the NIH scheme underestimates the risk of small bowel tumours and overestimates those of gastric origin. It is now widely held that this scheme should be replaced by one derived from the data collected by Lasota and Miettinen (Miettinen & Lasota, 2006a) (Table 4).

This scheme requires validation on independent data. Based on tumour size (maximum dimension in cm) and mitotic activity (number of mitoses per 50 HPFs), the categories of prognosis are defined as follows:


Table 4. Risk stratification of GIST by mitotic count, tumour size and anatomic site (Miettinen & Lasota, 2006a).

## **11.1.3 Resection margins**

The principal treatment for GISTs is surgery with wide local resection including a margin of 10–20mm for most tumours. Radical resection such as total gastrectomy with lymphadenectomy is not required. Involvement of the circumferential and surgical margins indicates a higher likelihood of local recurrence and therefore poorer outcome regardless of all other factors.

## **11.1.4 Epithelioid morphology**

This cellular pattern is present in one third of gastric tumours, but is usually associated with more aggressive behaviour when found in the small intestine.

## **11.1.5 Mucosal invasion**

Mucosal invasion is rarely seen in GISTs but is an adverse prognostic sign (Goldblum & Appelman, 1995) as it is confined to malignant GISTs (Miettinen et al., 2002a). Mucosal invasion should be distinguished from mucosal ulceration by its diffuse "lymphoma-like" pattern of growth between the glandular elements (Miettinen et al., 2002a). The presence of mucosal ulceration has no prognostic significance as it is found in benign and malignant GISTs

## **11.1.6 Cellularity**

190 Soft Tissue Tumors

A scheme proposed under the aegis of the National Institutes of Health (NIH) defined the risk of aggressive behaviour using the twin criteria of tumour size and mitotic activity count irrespective of tumour location. A significant body of opinion holds that the NIH scheme underestimates the risk of small bowel tumours and overestimates those of gastric origin. It is now widely held that this scheme should be replaced by one derived from the data

This scheme requires validation on independent data. Based on tumour size (maximum dimension in cm) and mitotic activity (number of mitoses per 50 HPFs), the categories of

Tumour Parameters Risk of progressive disease (metastasis or tumour-related death)

data

data

Table 4. Risk stratification of GIST by mitotic count, tumour size and anatomic site

Insufficient data

The principal treatment for GISTs is surgery with wide local resection including a margin of 10–20mm for most tumours. Radical resection such as total gastrectomy with lymphadenectomy is not required. Involvement of the circumferential and surgical margins indicates a higher likelihood of local recurrence and therefore poorer outcome regardless of

This cellular pattern is present in one third of gastric tumours, but is usually associated with

Mucosal invasion is rarely seen in GISTs but is an adverse prognostic sign (Goldblum & Appelman, 1995) as it is confined to malignant GISTs (Miettinen et al., 2002a). Mucosal invasion should be distinguished from mucosal ulceration by its diffuse "lymphoma-like" pattern of growth between the glandular elements (Miettinen et al., 2002a). The presence of

>10 cm High (86%) High (86%) High (90%) High (71%)

Size Gastric Duodenum Jejenum/Ileum Rectum ≤ 2cm None (0%) None (0%) None (0%) None (0%)

Low (8.3%) Low (4.3%) Low (8.5%)

High (34%) High (52%) High (57%)

High (limited

High (50%) High (73%) High (52%)

data)

Moderate (24%) Insufficient

High (85%) Insufficient

data

data

High (54%)

collected by Lasota and Miettinen (Miettinen & Lasota, 2006a) (Table 4).

prognosis are defined as follows:

>2 - ≤5 Very low

>10 cm Moderate (10%)

≤ 2cm Insufficient data

>2 - ≤5 Moderate (16%)

(Miettinen & Lasota, 2006a).

**11.1.3 Resection margins** 

**11.1.4 Epithelioid morphology** 

**11.1.5 Mucosal invasion** 

all other factors.

(1.9%)

>5 - ≤10 Low (3.6%) Insufficient

>5 - ≤10 High (55%) Insufficient

more aggressive behaviour when found in the small intestine.

Mitotic index ≤5/50HPFs

Mitotic index >5/50 HPFs Low cellularity has emerged as a favourable prognostic feature according to some studies (Goldblum & Appelman, 1995).

#### **11.1.7 Nuclear pleomorphism**

Marked nuclear pleomorphism in a spindle cell tumour suggests a malignant behavior, on the other hand, scattered bizarre multinucleated cells are characteristic of benign lesions.

## **11.1.8 Immunohistochemical markers**

Proliferation markers (Ki-67, MIB-1 and proliferating cell nuclear antigen (PCNA)) may aid in tumour evaluation. It has been reported that tumours with more than 10% of nuclei for Ki-67 analogue are associated with metastases and poor survival rate (Amin et al., 1993; Panizo-Santos et al., 2000; Reith et al., 2000; Rudolph et al., 1998; Wang et al., 2002). One study has reported that MIB-1 index was not superior to mitotic count as a prognostic factor (Wong et al., 2003).

Alterations affecting certain cell cycle regulators have been implicated in the pathogenesis and tumour progression of many tumours.

The tumour suppressor gene *p16INK4* encodes a nuclear protein that belongs to the INK4A family of cyclin dependent kinase inhibitors and blocks cell cycle progression at the G1-S transition (Serrano et al., 1993). It has been reported that loss of p16 immunostaining is associated with high risk GISTs (Haller et al., 2005; Liang et al., 2007; Ricci et al., 2004; Sabah et al., 2004b; Sabah et al., 2006; Schneider-Stock et al., 2003; Schneider-Stock et al., 2005; Steigen et al., 2008).

Another gene*, p27KIP1* is also a cyclin dependent kinase inhibitor that belongs to the CIP/ KIP family. An inverse correlation between p27KIP1 protein expression and the degree of malignancy has been observed. Low p27KIP1 expression seems to be associated with aggressive clinical behaviour in GISTs (Gelen et al., 2003; Nemoto et al., 2006; Pruneri et al., 2003; Sabah et al., 2006).

E2F1 is a transcription factor. Phosphorylation of the Rb protein results in the release of E2F proteins, that are necessary for progression into S phase. Expression of E2F1 has been reported to be an adverse prognostic factor (Haller et al., 2005; Sabah et al., 2006).

Finally, the expression of p53, a transcription factor and a cell cycle regulator, has been extensively investigated in human malignancies including GISTs. Most studies have suggested that p53 expression correlates with histologically malignant GISTs (Al Bozom, 2001; Cunningham et al., 2001; Feakins, 2005; Gumurdulu et al., 2007; Haller et al., 2005; Hata et al., 2006; Hillemanns et al., 1998; Ryu et al., 2007; Sabah et al., 2006; Wang & Kou, 2007; Wang et al., 2002; Wong et al., 2003; Yalcinkaya et al., 2007).

#### **11.2 Cytogenetic markers as prognostic factors**

Prediction of clinical outcome on the basis of morphology alone is not always reliable. Other new and promising parameters that may aid prognostic evaluation may emerge from genetic studies.

Gastrointestinal Stromal Tumours:

al., 2004a).

A Contemporary Review on Pathogenesis, Morphology and Prognosis 193

cells do not express telomerase. Telomerase activity has been detected exclusively in malignant GISTs (Gunther et al., 2000; Sakurai et al., 1998; Wang & Kou, 2007). The expression of human telomerase reverse transcriptase (hTERT) by immunohistochemistry was investigated and was found that hTERT expression occurs preferentially in malignant GISTs and that the signal intensity correlated with the mitotic count of the tumour (Sabah et

Fig. 5. Molecular events involved in the tumourigenesis of GISTs and chromosomal losses

Several radiological techniques are used to image GISTs. These include double contrast gastrointestinal X-ray series with barium, endoscopic ultrasound, computed tomography scanning and magnetic resonance. These modalities allow preoperative assessment of the size and involvement of other structures. They are also useful in identifying metastatic

Recently positron emission tomography (PET) scanning has been shown to be a useful and non-invasive mean of monitoring effectiveness of treatment of GISTs. Moreover, GIST response assessed by PET scan eight days after the start of imatinib mesylate treatment correlates with prognosis and survival at one year in patients with non-resectable GIST

and gains involved in the progression of GISTs.

**12. Imaging** 

lesions.

(Stroobants et al., 2003).

#### **11.2.1 Mutations of** *c-kit* **and** *PDGFRA*

Both are known to be critical steps in initiating primary oncogenic events. The prognostic value and the therapeutic significance of *c-kit* mutations remain under investigation.

The presence of deletion/insertion mutations involving exon 11 has been identified as an independent negative predictor of disease-free survival (Lasota et al., 1999; Martin et al., 2005; Singer et al., 2002). In addition the type of *c-kit* mutation was found to be of prognostic relevance. For instance deletions; particularly deletions affecting codon 557 to 558 indicate a poor prognosis (Antonescu, 2006; Martin et al., 2005). In contrast, GIST patients harbouring point mutations or internal tandem duplications, follow a more indolent clinical course (Antonescu, 2006; Corless, 2004; Corless et al., 2004; Martin et al., 2005; Miettinen et al., 2005; Wardelmann et al., 2003).

Moreover an association between KIT exon 9 mutations and aggressive behaviour and non gastric site was reported (Antonescu et al., 2003; Corless et al., 2004).

It has been shown that the type of kinase receptor mutation influences response to imatinib treatment. Patients with GISTs expressing mutant exon 11 isoforms have a better response to STI-571 compared with patients harbouring mutations in exon 9 or without detectable *c-kit*  or *PDGFRA* mutations (Heinrich et al., 2003a). In contrast, tumours with exon 17 or exon 13 mutations are primarily resistant to STI-571 (Chen et al., 2004; Debiec-Rychter et al., 2004a; Heinrich et al., 2003a; Tornillo & Terracciano, 2006). Similarly, mutations in exon 12 of *PDGFRA* have shown in vivo sensitivity to STI-571 compared with *PDGFRA* exon 18 (Debiec-Rychter et al., 2004a) which are resistant to both imatinib and sunitinib.

#### **11.2.2 Chromosomal losses and gains**

Certain cytogenetic aberrations have been identified in benign, malignant and metastatic GISTs, irrespective of their sites or degree of differentiation (Breiner et al., 2000; El Rifai et al., 1996; El Rifai et al., 2000; Gunawan et al., 2002; Kim et al., 2000; Lasota et al., 2005; Sandberg & Bridge, 2002; Sarlomo-Rikala et al., 1998; Wozniak et al., 2007), suggesting that these changes are early events in GIST tumourigenesis. These include losses at chromosome arms 14q and 22q.

Cytogenetic studies have reported correlations between the acquisition of additional chromosomal changes and aggressive behaviour such as gains at 5p and 20q and losses at chromosomes 1p, 9q and 9p. Gains at 8q and 17q have been detected in metastatic GISTs far more frequently than in primary tumours (Breiner et al., 2000; Debiec-Rychter et al., 2001; Derre et al., 2001; Gunawan et al., 2004; Kim et al., 2000; Miettinen et al., 2002a; O'Leary et al., 1999). Therefore, these chromosomal aberrations appear to be secondary events and may play an important role in tumour progression (Heinrich et al., 2003a) (Figure 5).

The loss of heterozygosity of the 9p region in malignant and low malignant potential GISTs has been investigated. It has been shown that loss of heterozygosity at the 9p region was absent in low malignant potential GISTs but was a common finding in high risk tumours (malignant and recurrent group). Recurrent GISTs showed more frequent deletions than their primary tumours (Sabah et al., 2004b). These findings support the theory that loss of 9p may contribute to the progression and/or malignant transformation of GISTs.

#### **11.2.3 Telomerase activity**

Telomerase is an enzyme that extends telomeric repeats on the ends of eukaryotic chromosomes, protecting them from loss, fusion and degradation. Most normal somatic cells do not express telomerase. Telomerase activity has been detected exclusively in malignant GISTs (Gunther et al., 2000; Sakurai et al., 1998; Wang & Kou, 2007). The expression of human telomerase reverse transcriptase (hTERT) by immunohistochemistry was investigated and was found that hTERT expression occurs preferentially in malignant GISTs and that the signal intensity correlated with the mitotic count of the tumour (Sabah et al., 2004a).

Fig. 5. Molecular events involved in the tumourigenesis of GISTs and chromosomal losses and gains involved in the progression of GISTs.

## **12. Imaging**

192 Soft Tissue Tumors

Both are known to be critical steps in initiating primary oncogenic events. The prognostic

The presence of deletion/insertion mutations involving exon 11 has been identified as an independent negative predictor of disease-free survival (Lasota et al., 1999; Martin et al., 2005; Singer et al., 2002). In addition the type of *c-kit* mutation was found to be of prognostic relevance. For instance deletions; particularly deletions affecting codon 557 to 558 indicate a poor prognosis (Antonescu, 2006; Martin et al., 2005). In contrast, GIST patients harbouring point mutations or internal tandem duplications, follow a more indolent clinical course (Antonescu, 2006; Corless, 2004; Corless et al., 2004; Martin et al., 2005; Miettinen et al., 2005;

Moreover an association between KIT exon 9 mutations and aggressive behaviour and non

It has been shown that the type of kinase receptor mutation influences response to imatinib treatment. Patients with GISTs expressing mutant exon 11 isoforms have a better response to STI-571 compared with patients harbouring mutations in exon 9 or without detectable *c-kit*  or *PDGFRA* mutations (Heinrich et al., 2003a). In contrast, tumours with exon 17 or exon 13 mutations are primarily resistant to STI-571 (Chen et al., 2004; Debiec-Rychter et al., 2004a; Heinrich et al., 2003a; Tornillo & Terracciano, 2006). Similarly, mutations in exon 12 of *PDGFRA* have shown in vivo sensitivity to STI-571 compared with *PDGFRA* exon 18

Certain cytogenetic aberrations have been identified in benign, malignant and metastatic GISTs, irrespective of their sites or degree of differentiation (Breiner et al., 2000; El Rifai et al., 1996; El Rifai et al., 2000; Gunawan et al., 2002; Kim et al., 2000; Lasota et al., 2005; Sandberg & Bridge, 2002; Sarlomo-Rikala et al., 1998; Wozniak et al., 2007), suggesting that these changes are early events in GIST tumourigenesis. These include losses at chromosome

Cytogenetic studies have reported correlations between the acquisition of additional chromosomal changes and aggressive behaviour such as gains at 5p and 20q and losses at chromosomes 1p, 9q and 9p. Gains at 8q and 17q have been detected in metastatic GISTs far more frequently than in primary tumours (Breiner et al., 2000; Debiec-Rychter et al., 2001; Derre et al., 2001; Gunawan et al., 2004; Kim et al., 2000; Miettinen et al., 2002a; O'Leary et al., 1999). Therefore, these chromosomal aberrations appear to be secondary events and may

The loss of heterozygosity of the 9p region in malignant and low malignant potential GISTs has been investigated. It has been shown that loss of heterozygosity at the 9p region was absent in low malignant potential GISTs but was a common finding in high risk tumours (malignant and recurrent group). Recurrent GISTs showed more frequent deletions than their primary tumours (Sabah et al., 2004b). These findings support the theory that loss of 9p

Telomerase is an enzyme that extends telomeric repeats on the ends of eukaryotic chromosomes, protecting them from loss, fusion and degradation. Most normal somatic

gastric site was reported (Antonescu et al., 2003; Corless et al., 2004).

(Debiec-Rychter et al., 2004a) which are resistant to both imatinib and sunitinib.

play an important role in tumour progression (Heinrich et al., 2003a) (Figure 5).

may contribute to the progression and/or malignant transformation of GISTs.

value and the therapeutic significance of *c-kit* mutations remain under investigation.

**11.2.1 Mutations of** *c-kit* **and** *PDGFRA*

**11.2.2 Chromosomal losses and gains** 

Wardelmann et al., 2003).

arms 14q and 22q.

**11.2.3 Telomerase activity** 

Several radiological techniques are used to image GISTs. These include double contrast gastrointestinal X-ray series with barium, endoscopic ultrasound, computed tomography scanning and magnetic resonance. These modalities allow preoperative assessment of the size and involvement of other structures. They are also useful in identifying metastatic lesions.

Recently positron emission tomography (PET) scanning has been shown to be a useful and non-invasive mean of monitoring effectiveness of treatment of GISTs. Moreover, GIST response assessed by PET scan eight days after the start of imatinib mesylate treatment correlates with prognosis and survival at one year in patients with non-resectable GIST (Stroobants et al., 2003).

Gastrointestinal Stromal Tumours:

the prognostication of GISTS in the future.

*Histopathology, 46,* 470-472.

*Med., 101,* 373-377.

*Semin.Diagn.Pathol., 23,* 120-129.

outlook for GIST patients.

**15. References** 

523.

**14. Conclusion** 

A Contemporary Review on Pathogenesis, Morphology and Prognosis 195

GISTs constitute the largest group of mesenchymal tumours of the gastrointestinal tract. These tumours originate from the ICC or their precursors. Most GISTs express KIT and have gain of function mutations of *c-kit* or *PDGFRA*. Therefore, KIT expression has emerged as an important defining feature for these tumours. However, KIT expression is not specific for GISTs and should be interpreted in the context of clinical setting and appropriate morphology. A minority of GISTs are negative for KIT. In such cases, analysis of *c-kit o*r *PDGFRA* genes is necessary for accurate diagnosis. Clinically and pathologically, GISTs represent a spectrum of tumours that include benign, malignant and borderline variants. Prognostic features indicative of malignancy or high risk for aggressive clinical behaviour are generally identified by increased tumour size and mitotic activity in the context of tumour location. Cytogenetic parameters aid prognostic evaluation and may play a role in

Imatinib has revolutionised the management of advanced and metastatic GISTs. Alternative therapeutic strategies are currently being evaluated. These may benefit patients who are refractory to imatinib or may be useful as adjuvant/neoadjuvant therapy to improve the

Abdulkader, I., Cameselle-Teijeiro, J., & Forteza, J. (2005). Pathological changes related to

Agaimy, A., Wunsch, P. H., Sobin, L. H., Lasota, J., & Miettinen, M. (2006). Occurrence of

Al Bozom, I. A. (2001). p53 expression in gastrointestinal stromal tumors. *Pathol.Int., 51,* 519-

Amin, M. B., Ma, C. K., Linden, M. D., Kubus, J. J., & Zarbo, R. J. (1993). Prognostic value of

Antonescu, C. R. (2006). Gastrointestinal stromal tumor (GIST) pathogenesis, familial GIST,

Antonescu, C. R., Sommer, G., Sarran, L., Tschernyavsky, S. J., Riedel, E., Woodruff, J. M. et

Appelman, H. D. (1977). Cellular leiomyomas of the stomach in 49 patients. *Arch.Pathol Lab* 

Bauer, S., Yu, L. K., Demetri, G. D., & Fletcher, J. A. (2006). Heat shock protein 90 inhibition in imatinib-resistant gastrointestinal stromal tumor. *Cancer Res., 66,* 9153-9161. Besmer, P., Lader, E., George, P. C., Bergold, P. J., Qiu, F. H., Zuckerman, E. E. et al. (1986).

mitotic count and clinical outcome. *Am.J.Clin.Pathol, 100,* 428-432.

gastrointestinal stromal tumors. *Clin.Cancer Res., 9,* 3329-3337.

and animal models. *Semin.Diagn.Pathol., 23,* 63-69.

sarcoma virus v-fms protein. *J.Virol., 60,* 194-203.

Imatinib treatment in a patient with a metastatic gastrointestinal stromal tumour.

other malignancies in patients with gastrointestinal stromal tumors.

proliferating cell nuclear antigen index in gastric stromal tumors. Correlation with

al. (2003). Association of KIT exon 9 mutations with nongastric primary site and aggressive behavior: KIT mutation analysis and clinical correlates of 120

A new acute transforming feline retrovirus with fms homology specifies a Cterminally truncated version of the c-fms protein that is different from SM-feline

## **13. Treatment options**

Until recently surgery was the only effective treatment for GISTs and complete surgical resection is still the only treatment that can cure the disease. However even for patients whose tumour was completely removed with clear margins there is still high probability of local recurrence.

Treatment options for recurrent or metastatic GISTs are even more limited. Radiation therapy is rarely used to treat GISTs because of the radio-sensitivity of adjacent organs and the high radio-resistance of these tumours. GISTs are highly resistant to conventional chemotherapy, regardless of the agent used. The reasons for this are not fully understood but may relate to the expression of the multidrug resistance protein products of the *MDR1*  gene.

This bleak prognostic picture for patients with metastatic GISTs has recently changed with the advent of the tyrosine kinase inhibitor (STI-571, Imatinib mesylate). This drug binds to the ATP binding site of the target kinase and interrupts the signal transduction (Dematteo et al., 2002; Heinrich et al., 2002).

Imatinib is currently the first line agent for metastatic and unresectable GISTs and is currently under trial to test its possible effect of minimising the risk of recurrence in patients with high risk GISTs following complete resection (Dematteo et al., 2002). However, there is an ongoing debate on the duration, dose and the selection of patients for adjuvant therapy.

The effects of imatinib on GISTs morphology include reduction in tumour size, loss of cellularity, decreased mitoses or Ki67 proliferation index, degenerative changes such as myxoid stroma, cyst formation, necrosis and haemorrhage (Abdulkader et al., 2005; Loughrey et al., 2005; Pauwels et al., 2005). Additional potential diagnostic pitfalls include a possible shift from spindled to epithelioid morphology, loss of KIT and CD34 immunoreactivity (Abdulkader et al., 2005; Loughrey et al., 2005; Pauwels et al., 2005; Sciot & Debiec-Rychter, 2006) and positive desmin immunostaining in a tumours which were previously completely negative for desmin (Sciot & Debiec-Rychter, 2006).

Some 90% of patients obtain symptomatic relief. About two thirds achieve an objective response, as defined by a reduction of 50% or greater in tumour volume (van Oosterom et al., 2001). Another 20% of patients remain stable. However, in 10% the disease progresses despite of imatinib therapy due the occurrence of secondary mutations or clonal selection which cause drug resistance.

In such cases other tyrosine kinase inhibitors or downstream targets such as protein kinase theta can be tried (Sakamoto, 2004). Sunitinib malate (SU11248) has shown promising activity in imatinib resistant GISTs. In addition to KIT and PDGFRA, this drug also targets FLT3 and VEGF receptors (Demetri et al., 2003; Sakamoto, 2004).

Other drugs that are being evaluated in imatinib-refractory patients include Nilotinib (Montemurro et al., 2009) (inhibitor of KIT and PDGFRA); Sorafenib (a multi kinase inhibitor of raf kinase, VEGFR, PDGFR and KIT)(Demetri, 2011); RAD001 (a rapamycin analogue inhibitor of the protein kinase mammalian target of rapamycin); Oblimersen (an antisense oligonucleotide to bcl-2 mRNA); heat shock protein 90 inhibitor (17-allyylamino-18-demethoxy-geldanamycin, 17-AAG) (Bauer et al., 2006); Bevacizumab (a neutralising antibody to vascular endothelial growth factor); CCI 779 (a rapamycin analogue inhibitor of the protein kinase mammalian target of rapamycin); PKC 412 (an inhibitor of protein kinase C) and neutralising antibodies against vascular endothelial growth factor and several multi kinase inhibitors (De Giorgi & Verweij, 2005; Rubin, 2006).

## **14. Conclusion**

194 Soft Tissue Tumors

Until recently surgery was the only effective treatment for GISTs and complete surgical resection is still the only treatment that can cure the disease. However even for patients whose tumour was completely removed with clear margins there is still high probability of

Treatment options for recurrent or metastatic GISTs are even more limited. Radiation therapy is rarely used to treat GISTs because of the radio-sensitivity of adjacent organs and the high radio-resistance of these tumours. GISTs are highly resistant to conventional chemotherapy, regardless of the agent used. The reasons for this are not fully understood but may relate to the expression of the multidrug resistance protein products of the *MDR1* 

This bleak prognostic picture for patients with metastatic GISTs has recently changed with the advent of the tyrosine kinase inhibitor (STI-571, Imatinib mesylate). This drug binds to the ATP binding site of the target kinase and interrupts the signal transduction (Dematteo et

Imatinib is currently the first line agent for metastatic and unresectable GISTs and is currently under trial to test its possible effect of minimising the risk of recurrence in patients with high risk GISTs following complete resection (Dematteo et al., 2002). However, there is an ongoing debate on the duration, dose and the selection of patients for adjuvant therapy. The effects of imatinib on GISTs morphology include reduction in tumour size, loss of cellularity, decreased mitoses or Ki67 proliferation index, degenerative changes such as myxoid stroma, cyst formation, necrosis and haemorrhage (Abdulkader et al., 2005; Loughrey et al., 2005; Pauwels et al., 2005). Additional potential diagnostic pitfalls include a possible shift from spindled to epithelioid morphology, loss of KIT and CD34 immunoreactivity (Abdulkader et al., 2005; Loughrey et al., 2005; Pauwels et al., 2005; Sciot & Debiec-Rychter, 2006) and positive desmin immunostaining in a tumours which were

Some 90% of patients obtain symptomatic relief. About two thirds achieve an objective response, as defined by a reduction of 50% or greater in tumour volume (van Oosterom et al., 2001). Another 20% of patients remain stable. However, in 10% the disease progresses despite of imatinib therapy due the occurrence of secondary mutations or clonal selection

In such cases other tyrosine kinase inhibitors or downstream targets such as protein kinase theta can be tried (Sakamoto, 2004). Sunitinib malate (SU11248) has shown promising activity in imatinib resistant GISTs. In addition to KIT and PDGFRA, this drug also targets

Other drugs that are being evaluated in imatinib-refractory patients include Nilotinib (Montemurro et al., 2009) (inhibitor of KIT and PDGFRA); Sorafenib (a multi kinase inhibitor of raf kinase, VEGFR, PDGFR and KIT)(Demetri, 2011); RAD001 (a rapamycin analogue inhibitor of the protein kinase mammalian target of rapamycin); Oblimersen (an antisense oligonucleotide to bcl-2 mRNA); heat shock protein 90 inhibitor (17-allyylamino-18-demethoxy-geldanamycin, 17-AAG) (Bauer et al., 2006); Bevacizumab (a neutralising antibody to vascular endothelial growth factor); CCI 779 (a rapamycin analogue inhibitor of the protein kinase mammalian target of rapamycin); PKC 412 (an inhibitor of protein kinase C) and neutralising antibodies against vascular endothelial growth factor and several multi

previously completely negative for desmin (Sciot & Debiec-Rychter, 2006).

FLT3 and VEGF receptors (Demetri et al., 2003; Sakamoto, 2004).

kinase inhibitors (De Giorgi & Verweij, 2005; Rubin, 2006).

**13. Treatment options** 

al., 2002; Heinrich et al., 2002).

which cause drug resistance.

local recurrence.

gene.

GISTs constitute the largest group of mesenchymal tumours of the gastrointestinal tract. These tumours originate from the ICC or their precursors. Most GISTs express KIT and have gain of function mutations of *c-kit* or *PDGFRA*. Therefore, KIT expression has emerged as an important defining feature for these tumours. However, KIT expression is not specific for GISTs and should be interpreted in the context of clinical setting and appropriate morphology. A minority of GISTs are negative for KIT. In such cases, analysis of *c-kit o*r *PDGFRA* genes is necessary for accurate diagnosis. Clinically and pathologically, GISTs represent a spectrum of tumours that include benign, malignant and borderline variants.

Prognostic features indicative of malignancy or high risk for aggressive clinical behaviour are generally identified by increased tumour size and mitotic activity in the context of tumour location. Cytogenetic parameters aid prognostic evaluation and may play a role in the prognostication of GISTS in the future.

Imatinib has revolutionised the management of advanced and metastatic GISTs. Alternative therapeutic strategies are currently being evaluated. These may benefit patients who are refractory to imatinib or may be useful as adjuvant/neoadjuvant therapy to improve the outlook for GIST patients.

## **15. References**


Gastrointestinal Stromal Tumours:

477.

A Contemporary Review on Pathogenesis, Morphology and Prognosis 197

Debiec-Rychter, M., Wasag, B., Stul, M., De Wever, I., van Oosterom, A., Hagemeijer, A. et

Dematteo, R. P., Heinrich, M. C., El Rifai, W. M., & Demetri, G. (2002). Clinical management

Dematteo, R. P., Lewis, J. J., Leung, D., Mudan, S. S., Woodruff, J. M., & Brennan, M. F.

Demetri, G. D., George, S., Heinrich, M. C., & et al. (2003). Clinical activity and tolerability of

Demetri, G. D. (2011). Differential properties of current tyrosine kinase inhibitors in

Derre, J., Lagace, R., Terrier, P., Sastre, X., & Aurias, A. (2001). Consistent DNA losses on the

Dow, N., Giblen, G., Sobin, L. H., & Miettinen, M. (2006). Gastrointestinal stromal tumors:

Duensing, A., Joseph, N. E., Medeiros, F., Smith, F., Hornick, J. L., Heinrich, M. C. et al.

El Rifai, W., Sarlomo-Rikala, M., Andersson, L. C., Knuutila, S., & Miettinen, M. (2000). DNA

El Rifai, W., Sarlomo-Rikala, M., Miettinen, M., Knuutila, S., & Andersson, L. C. (1996). DNA

Emory, T. S., Sobin, L. H., Lukes, L., Lee, D. H., & O'Leary, T. J. (1999). Prognosis of

Espinosa, I., Lee, C. H., Kim, M. K., Rouse, B. T., Subramanian, S., Montgomery, K. et al.

marker for gastrointestinal stromal tumors. *Am.J.Surg.Pathol., 32,* 210-218. Feakins, R. M. (2005). The expression of p53 and bcl-2 in gastrointestinal stromal tumours is

Fletcher, C. D., Berman, J. J., Corless, C., Gorstein, F., Lasota, J., Longley, B. J. et al. (2002a).

Fletcher, C. D., Berman, J. J., Corless, C., Gorstein, F., Lasota, J., Longley, B. J. et al. (2002b).

Fletcher, C. D. & Fletcher, J. A. (2002). Testing for KIT (CD117) in gastrointestinal stromal

tumors: another HercepTest? *Am.J.Clin.Pathol, 118,* 163-164.

gastrointestinal stromal tumors. *Semin.Oncol., 38 Suppl 1,* S10-S19.

gastrointestinal stromal tumors (GISTs). *Cancer Res., 64,* 5127-5131.

progression and prognostic significance. *Cancer Res., 60,* 3899-3903.

antigen) immunoreactivity. *J.Pathol, 202,* 430-438.

prognostic factors for survival. *Ann.Surg, 231,* 51-58.

Proc.Am.Soc.Clin.Oncol 22[814], abstract (3273).

differential diagnosis. *Semin.Diagn.Pathol., 23,* 111-119.

*Cancer Genet.Cytogenet., 127,* 30-33.

tumors. *Cancer Res., 56,* 3230-3233.

clinical outcome. *Histopathology, 46,* 270-279.

*Am.J.Surg.Pathol., 23,* 82-87.

*Int.J.Surg.Pathol., 10,* 81-89.

*33,* 459-465.

al. (2004b). Gastrointestinal stromal tumours (GISTs) negative for KIT (CD117

of gastrointestinal stromal tumors: before and after STI-571. *Hum.Pathol., 33,* 466-

(2000). Two hundred gastrointestinal stromal tumors: recurrence patterns and

the multi-targated tyrosine kinase inhibitor SU11248 in patients with metastatic gastrointestinal stromal tumour refractory to imatinib mesylate.

short arm of chromosome 1 in a series of malignant gastrointestinal stromal tumors.

(2004). Protein Kinase C theta (PKCtheta) expression and constitutive activation in

sequence copy number changes in gastrointestinal stromal tumors: tumor

copy number losses in chromosome 14: an early change in gastrointestinal stromal

gastrointestinal smooth-muscle (stromal) tumors: dependence on anatomic site.

(2008). A novel monoclonal antibody against DOG1 is a sensitive and specific

associated with anatomical site, and p53 expression is associated with grade and

Diagnosis of gastrointestinal stromal tumors: A consensus approach. *Hum.Pathol.,* 

Diagnosis of gastrointestinal stromal tumors: a consensus approach.


Blay, P., Astudillo, A., Buesa, J. M., Campo, E., Abad, M., Garcia-Garcia, J. et al. (2004).

not in other mesenchymal neoplasias. *Clin.Cancer Res., 10,* 4089-4095. Breiner, J. A., Meis-Kindblom, J., Kindblom, L. G., McComb, E., Liu, J., Nelson, M. et al.

Bussolati, G. (2005). Of GISTs and EGISTs, ICCs and ICs. *Virchows Arch., 447,* 907-908. Carney, J. A. (1999). Gastric stromal sarcoma, pulmonary chondroma, and extra-adrenal

possible familial occurrence. *Mayo Clin.Proc., 74,* 543-552.

gastrointestinal stromal tumors. *Cancer Res., 64,* 5913-5919.

role for molecular testing. *Am.J.Clin.Pathol., 122,* 11-13.

vitro sensitivity to imatinib. *J.Clin.Oncol., 23,* 5357-5364.

we go from here? *Mol.Cancer Ther., 4,* 495-501.

and multiple gastrointestinal stromal tumours. *Gut, 51,* 793-796.

tumors). *Cancer Genet.Cytogenet., 120,* 111-116.

stromal tumor. *Gastroenterology, 126,* 318-321.

tumors. *J.Clin.Oncol., 22,* 3813-3825.

size. *Am.J.Pathol., 160,* 1567-1572.

*Eur.J.Cancer, 40,* 689-695.

*Pathol, 25,* 1364-1371.

Protein kinase C theta is highly expressed in gastrointestinal stromal tumors but

(2000). Loss of 14q and 22q in gastrointestinal stromal tumors (pacemaker cell

paraganglioma (Carney Triad): natural history, adrenocortical component, and

nature of diffuse proliferation of interstitial cells of Cajal in patients with familial

missense mutation in KIT kinase domain 1 correlates with imatinib resistance in

PDGFRA germline mutation in a family with multiple cases of gastrointestinal

Anaplastic lymphoma kinase (ALK) expression in the inflammatory myofibroblastic tumor: a comparative immunohistochemical study. *Am.J.Surg* 

are common in incidental gastrointestinal stromal tumors one centimeter or less in

PDGFRA mutations in gastrointestinal stromal tumors: frequency, spectrum and in

J. (2001). Apoptosis, bcl-2 expression, and p53 expression in gastrointestinal stromal/smooth muscle tumors. *Appl.Immunohistochem.Mol.Morphol., 9,* 19-23. De Giorgi, U. & Verweij, J. (2005). Imatinib and gastrointestinal stromal tumors: Where do

Use of c-KIT/PDGFRA mutational analysis to predict the clinical response to imatinib in patients with advanced gastrointestinal stromal tumours entered on phase I and II studies of the EORTC Soft Tissue and Bone Sarcoma Group.

Chromosomal aberrations in malignant gastrointestinal stromal tumors: correlation

Chen, H., Hirota, S., Isozaki, K., Sun, H., Ohashi, A., Kinoshita, K. et al. (2002). Polyclonal

Chen, L. L., Trent, J. C., Wu, E. F., Fuller, G. N., Ramdas, L., Zhang, W. et al. (2004). A

Chompret, A., Kannengiesser, C., Barrois, M., Terrier, P., Dahan, P., Tursz, T. et al. (2004).

Cook, J. R., Dehner, L. P., Collins, M. H., Ma, Z., Morris, S. W., Coffin, C. M. et al. (2001).

Corless, C. L. (2004). Assessing the prognosis of gastrointestinal stromal tumors: a growing

Corless, C. L., Fletcher, J. A., & Heinrich, M. C. (2004). Biology of gastrointestinal stromal

Corless, C. L., McGreevey, L., Haley, A., Town, A., & Heinrich, M. C. (2002). KIT mutations

Corless, C. L., Schroeder, A., Griffith, D., Town, A., McGreevey, L., Harrell, P. et al. (2005).

Cunningham, R. E., Abbondanzo, S. L., Chu, W. S., Emory, T. S., Sobin, L. H., & O'Leary, T.

Debiec-Rychter, M., Dumez, H., Judson, I., Wasag, B., Verweij, J., Brown, M. et al. (2004a).

Debiec-Rychter, M., Lasota, J., Sarlomo-Rikala, M., Kordek, R., & Miettinen, M. (2001).

with c-KIT gene mutation. *Cancer Genet.Cytogenet., 128,* 24-30.


Gastrointestinal Stromal Tumours:

*Science, 279,* 577-580.

326-327.

2089-2091.

1259-1269.

60.

stromal tumours. *J.Pathol., 193,* 505-510.

A Contemporary Review on Pathogenesis, Morphology and Prognosis 199

Hillemanns, M., Pasold, S., Bottcher, K., & Hofler, H. (1998). [Prognostic factors of

Hirota, S., Isozaki, K., Moriyama, Y., Hashimoto, K., Nishida, T., Ishiguro, S. et al. (1998).

Hirota, S., Nishida, T., Isozaki, K., Taniguchi, M., Nakamura, J., Okazaki, T. et al. (2001).

Hirota, S., Ohashi, A., Nishida, T., Isozaki, K., Kinoshita, K., Shinomura, Y. et al. (2003).

Hirota, S., Okazaki, T., Kitamura, Y., O'Brien, P., Kapusta, L., & Dardick, I. (2000). Cause of

Hornick, J. L. & Fletcher, C. D. (2007). The role of KIT in the management of patients with

Hostein, I., Longy, M., Gastaldello, B., Geneste, G., & Coindre, J. M. (2006). Detection of a

Hu, X., Forster, J., & Damjanov, I. (2003). Primary malignant gastrointestinal stromal tumor

Isozaki, K., Terris, B., Belghiti, J., Schiffmann, S., Hirota, S., & Vanderwinden, J. M. (2000).

Kang, D. Y., Park, C. K., Choi, J. S., Jin, S. Y., Kim, H. J., Joo, M. et al. (2007). Multiple

Kim, N. G., Kim, J. J., Ahn, J. Y., Seong, C. M., Noh, S. H., Kim, C. B. et al. (2000). Putative

Kindblom, L. G., Remotti, H. E., Aldenborg, F., & Meis-Kindblom, J. M. (1998).

Kinoshita, K., Isozaki, K., Hirota, S., Nishida, T., Chen, H., Nakahara, M. et al. (2003). c-kit

Lasota, J., Carlson, J. A., & Miettinen, M. (2000a). Spindle cell tumor of urinary bladder

Lasota, J., Jasinski, M., Sarlomo-Rikala, M., & Miettinen, M. (1999). Mutations in exon 11 of

gastrointestinal stromal tumors. *Gastroenterology, 125,* 660-667.

gastrointestinal stromal tumors. *Hum.Pathol., 38,* 679-687.

gastrointestinal stromal tumors. *Am.J.Pathol., 157,* 1581-1585.

gastrointestinal stromal tumors. *Int.J.Cancer, 85,* 633-638.

of the liver. *Arch.Pathol.Lab Med., 127,* 1606-1608.

patients. *Am.J.Surg.Pathol., 31,* 224-232.

tumors. *J.Gastroenterol.Hepatol., 18,* 147-151.

*Arch.Pathol.Lab Med., 124,* 894-897.

gastrointestinal stromal tumors of the stomach]. *Verh.Dtsch.Ges.Pathol., 82,* 261-266.

Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors.

Gain-of-function mutation at the extracellular domain of KIT in gastrointestinal

Gain-of-function mutations of platelet-derived growth factor receptor alpha gene in

familial and multiple gastrointestinal autonomic nerve tumors with hyperplasia of interstitial cells of Cajal is germline mutation of the c-kit gene. *Am.J.Surg.Pathol., 24,*

new mutation in KIT exon 9 in a gastrointestinal stromal tumor. *Int.J.Cancer, 118,*

Germline-activating mutation in the kinase domain of KIT gene in familial

gastrointestinal stromal tumors: Clinicopathologic and genetic analysis of 12

chromosomal deletions on 9P, 9Q and 22Q occur preferentially in malignant

Gastrointestinal pacemaker cell tumor (GIPACT): gastrointestinal stromal tumors show phenotypic characteristics of the interstitial cells of Cajal. *Am.J.Pathol., 152,*

gene mutation at exon 17 or 13 is very rare in sporadic gastrointestinal stromal

serosa with phenotypic and genotypic features of gastrointestinal stromal tumor.

c-Kit occur preferentially in malignant versus benign gastrointestinal stromal tumors and do not occur in leiomyomas or leiomyosarcomas. *Am.J.Pathol., 154,* 53-


Gelen, M. T., Elpek, G. O., Aksoy, N. H., Ogus, M., Suleymanlar, I., & Isitan, F. (2003). p27

Gengler, C. & Guillou, L. (2006). Solitary fibrous tumour and haemangiopericytoma:

Giuly, J. A., Picand, R., Giuly, D., Monges, B., & Nguyen-Cat, R. (2003a). Von Recklinghausen disease and gastrointestinal stromal tumors. *Am.J.Surg, 185,* 86-87. Goldblum, J. R. & Appelman, H. D. (1995). Stromal tumors of the duodenum. A histologic and immunohistochemical study of 20 cases. *Am.J.Surg.Pathol., 19,* 71-80. Golden T & Stout AP (1941). Smooth muscle tumours of the gastrointestinal tract and

Greenson, J. K. (2003). Gastrointestinal stromal tumors and other mesenchymal lesions of

Gumurdulu, D., Erdogan, S., Kayaselcuk, F., Seydaoglu, G., Parsak, C. K., Demircan, O. et al.

Gunawan, B., Bergmann, F., Hoer, J., Langer, C., Schumpelick, V., Becker, H. et al. (2002).

Gunawan, B., Schulten, H. J., von Heydebreck, A., Schmidt, B., Enders, C., Hoer, J. et al.

Gunther, T., Schneider-Stock, R., Hackel, C., Pross, M., Schulz, H. U., Lippert, H. et al.

Haller, F., Gunawan, B., von Heydebreck, A., Schwager, S., Schulten, H. J., Wolf-Salgo, J. et

Hata, Y., Ishigami, S., Natsugoe, S., Nakajo, A., Okumura, H., Miyazono, F. et al. (2006). P53

Heinrich, M. C., Corless, C. L., Demetri, G. D., Blanke, C. D., von Mehren, M., Joensuu, H. et

Heinrich, M. C., Corless, C. L., Duensing, A., McGreevey, L., Chen, C. J., Joseph, N. et al.

Heinrich, M. C., Rubin, B. P., Longley, B. J., & Fletcher, J. A. (2002). Biology and genetic

Herrera, G. A., Pinto de Moraes H., Grizzle, W. E., & Han, S. G. (1984). Malignant small

gastrointestinal stromal tumors. *Clin.Cancer Res., 11,* 6589-6597.

gastrointestinal stromal tumor. *J.Clin.Oncol., 21,* 4342-4349.

high-risk gastrointestinal stromal tumors. *Hum.Pathol., 33,* 316-321.

(2007). Expression of COX-2, PCNA, Ki-67 and p53 in gastrointestinal stromal tumors and its relationship with histopathological parameters. *World* 

Biological and clinical significance of cytogenetic abnormalities in low-risk and

(2004). Site-independent prognostic value of chromosome 9q loss in primary

(2000). Telomerase activity and expression of hTRT and hTR in gastrointestinal stromal tumors in comparison with extragastrointestinal sarcomas. *Clin.Cancer Res.,* 

al. (2005). Prognostic role of E2F1 and members of the CDKN2A network in

and MIB-1 expression in gastrointestinal stromal tumor (GIST) of the stomach.

al. (2003a). Kinase mutations and imatinib response in patients with metastatic

(2003b). PDGFRA activating mutations in gastrointestinal stromal tumors. *Science,* 

aspects of gastrointestinal stromal tumors: KIT activation and cytogenetic

bowel neoplasm of enteric plexus derivation (plexosarcoma). Light and electron microscopic study confirming the origin of the neoplasm. *Dig.Dis.Sci., 29,* 275-284.

*Turk.J.Gastroenterol., 14,* 132-137.

the gut. *Mod.Pathol., 16,* 366-375.

*Hepatogastroenterology, 53,* 613-615.

alterations. *Hum.Pathol., 33,* 484-495.

*J.Gastroenterol., 13,* 426-431.

*6,* 1811-1818.

*299,* 708-710.

evolution of a concept. *Histopathology, 48,* 63-74.

retroperitoneal tissues. *Surg Gynecol Obstet, 73,* 784-810.

gastrointestinal stromal tumours. *J.Pathol., 202,* 421-429.

expression and proliferation in gastrointestinal stromal tumors.


Gastrointestinal Stromal Tumours:

6198.

*126,* 481-483.

*130,* 1466-1478.

A Contemporary Review on Pathogenesis, Morphology and Prognosis 201

Maeyama, H., Hidaka, E., Ota, H., Minami, S., Kajiyama, M., Kuraishi, A. et al. (2001).

Martin, J., Poveda, A., Llombart-Bosch, A., Ramos, R., Lopez-Guerrero, J. A., Garcia del, M.

Matyakhina, L., Bei, T. A., McWhinney, S. R., Pasini, B., Cameron, S., Gunawan, B. et al.

Mazur, M. T. & Clark, H. B. (1983). Gastric stromal tumors. Reappraisal of histogenesis.

Medeiros, F., Corless, C. L., Duensing, A., Hornick, J. L., Oliveira, A. M., Heinrich, M. C. et

Mendoza-Marin, M., Hoang, M. P., & Albores-Saavedra J. (2002). Malignant stromal tumor

Miettinen, M., El Rifai, W., Sobin, H. L., & Lasota, J. (2002a). Evaluation of malignancy and prognosis of gastrointestinal stromal tumors: a review. *Hum.Pathol., 33,* 478-483. Miettinen, M. & Lasota, J. (2001). Gastrointestinal stromal tumors--definition, clinical,

Miettinen, M. & Lasota, J. (2006a). Gastrointestinal stromal tumors: pathology and prognosis

Miettinen, M. & Lasota, J. (2006b). Gastrointestinal stromal tumors: review on morphology,

Miettinen, M., Majidi, M., & Lasota, J. (2002b). Pathology and diagnostic criteria of

Miettinen, M., Makhlouf, H., Sobin, L. H., & Lasota, J. (2006). Gastrointestinal stromal

Miettinen, M., Monihan, J. M., Sarlomo-Rikala, M., Kovatich, A. J., Carr, N. J., Emory, T. S. et

Miettinen, M., Paal, E., Lasota, J., & Sobin, L. H. (2002c). Gastrointestinal glomus tumors: a

Miettinen, M., Sarlomo-Rikala, M., & Sobin, L. H. (2001). Mesenchymal tumors of

Miettinen, M. (2001). Are desmoid tumors kit positive? *Am.J.Surg.Pathol., 25,* 549-550.

germline mutation of the c-kit gene. *Gastroenterology, 120,* 210-215.

stromal tumors. *J.Clin.Endocrinol.Metab, 92,* 2938-2943.

therapeutic implications. *Am.J.Surg.Pathol., 28,* 889-894.

*Am.J.Surg.Pathol., 7,* 507-519.

diagnosis. *Virchows Arch., 438,* 1-12.

*Am.J.Surg.Pathol., 30,* 477-489.

*Am.J.Surg.Pathol., 26,* 301-311.

at different sites. *Semin.Diagn.Pathol., 23,* 70-83.

of 26 cases. *Am.J.Surg.Pathol., 23,* 1109-1118.

Familial gastrointestinal stromal tumor with hyperpigmentation: association with a

J. et al. (2005). Deletions affecting codons 557-558 of the c-KIT gene indicate a poor prognosis in patients with completely resected gastrointestinal stromal tumors: a study by the Spanish Group for Sarcoma Research (GEIS). *J.Clin.Oncol., 23,* 6190-

(2007). Genetics of carney triad: recurrent losses at chromosome 1 but lack of germline mutations in genes associated with paragangliomas and gastrointestinal

al. (2004). KIT-negative gastrointestinal stromal tumors: proof of concept and

of the gallbladder with interstitial cells of Cajal phenotype. *Arch.Pathol.Lab Med.,* 

histological, immunohistochemical, and molecular genetic features and differential

molecular pathology, prognosis, and differential diagnosis. *Arch.Pathol.Lab Med.,* 

gastrointestinal stromal tumors (GISTs): a review. *Eur.J.Cancer, 38 Suppl 5,* S39-S51.

tumors of the jejunum and ileum: a clinicopathologic, immunohistochemical, and molecular genetic study of 906 cases before imatinib with long-term follow-up.

al. (1999). Gastrointestinal stromal tumors/smooth muscle tumors (GISTs) primary in the omentum and mesentery: clinicopathologic and immunohistochemical study

clinicopathologic, immunohistochemical, and molecular genetic study of 32 cases.

muscularis mucosae of colon and rectum are benign leiomyomas that should be


Lasota, J., Kopczynski, J., Sarlomo-Rikala, M., Schneider-Stock, R., Stachura, T., Kordek, R. et

Lasota, J., Dansonka-Mieszkowska, A., Sobin, L. H., & Miettinen, M. (2004). A great majority

Lasota, J., Wasag, B., Dansonka-Mieszkowska, A., Karcz, D., Millward, C. L., Rys, J. et al.

Lasota, J., Wozniak, A., Kopczynski, J., Dansonka-Mieszkowska, A., Wasag, B., Mitsuhashi,

Lasota, J., Wozniak, A., Sarlomo-Rikala, M., Rys, J., Kordek, R., Nassar, A. et al. (2000b).

Lauwers, G. Y., Erlandson, R. A., Casper, E. S., Brennan, M. F., & Woodruff, J. M. (1993).

Lee, J. R., Joshi, V., Griffin, J. W., Jr., Lasota, J., & Miettinen, M. (2001). Gastrointestinal

Lespi, J. & Drut, R. (1997). [Gastrointestinal autonomic tumor associated with von

Li, F. P., Fletcher, J. A., Heinrich, M. C., Garber, J. E., Sallan, S. E., Curiel-Lewandrowski, C.

Liang, J. F., Zheng, H. X., Li, N., Cheng, C. X., Xiao, H., & Wang, H. K. (2007). [Prognostic

Longley, B. J., Reguera, M. J., & Ma, Y. (2001). Classes of c-KIT activating mutations:

Loughrey, M. B., Mitchell, C., Mann, G. B., Michael, M., & Waring, P. M. (2005).

Lucas, D. R., al-Abbadi, M., Tabaczka, P., Hamre, M. R., Weaver, D. W., & Mott, M. J. (2003).

evaluation of two commercial antibodies. *Am.J.Clin.Pathol., 119,* 339-345. Lux, M. L., Rubin, B. P., Biase, T. L., Chen, C. J., Maclure, T., Demetri, G. et al. (2000). KIT

stromal tumors (GISTs): a study on 50 cases. *Lab Invest, 85,* 237-247.

schwannomas: s study of 20 cases. *Lab Invest, 83,* 1361-1371.

tumors. A study of 200 cases. *Am.J.Pathol., 157,* 1091-1095.

gastrointestinal stromal tumor. *Am.J.Surg.Pathol., 25,* 979-987.

molecular features in a kindred. *J.Clin.Oncol., 23,* 2735-2743.

stromal tumor]. *Zhonghua Wei Chang Wai Ke.Za Zhi., 10,* 372-375.

Recklinghausen's disease]. *Acta Gastroenterol.Latinoam., 27,* 271-274.

tumors (GISTs). *Semin.Diagn.Pathol., 23,* 91-102.

potential. *Lab Invest, 84,* 874-883.

therapy. *Leuk.Res., 25,* 571-576.

*Am.J.Pathol., 156,* 791-795.

*58,* 779-781.

887-897.

al. (2003a). KIT 1530ins6 mutation defines a subset of predominantly malignant gastrointestinal stromal tumors of intestinal origin. *Hum.Pathol., 34,* 1306-1312. Lasota, J. & Miettinen, M. (2006). KIT and PDGFRA mutations in gastrointestinal stromal

of GISTs with PDGFRA mutations represent gastric tumors of low or no malignant

(2003b). Evaluation of NF2 and NF1 tumor suppressor genes in distinctive gastrointestinal nerve sheath tumors traditionally diagnosed as benign

T. et al. (2005). Loss of heterozygosity on chromosome 22q in gastrointestinal

Mutations in exons 9 and 13 of KIT gene are rare events in gastrointestinal stromal

Gastrointestinal autonomic nerve tumors. A clinicopathological, immunohistochemical, and ultrastructural study of 12 cases. *Am.J.Surg Pathol, 17,*

autonomic nerve tumor: immunohistochemical and molecular identity with

et al. (2005). Familial gastrointestinal stromal tumor syndrome: phenotypic and

value of P16 gene methylation and P16 protein expression in gastrointestinal

proposed mechanisms of action and implications for disease classification and

Gastrointestinal stromal tumour treated with neoadjuvant imatinib. *J.Clin.Pathol.,* 

c-Kit expression in desmoid fibromatosis. Comparative immunohistochemical

extracellular and kinase domain mutations in gastrointestinal stromal tumors.


Gastrointestinal Stromal Tumours:

A Contemporary Review on Pathogenesis, Morphology and Prognosis 203

Ohashi, A., Kinoshita, K., Isozaki, K., Nishida, T., Shinomura, Y., Kitamura, Y. et al. (2004).

Pasini, B., McWhinney, S. R., Bei, T., Matyakhina, L., Stergiopoulos, S., Muchow, M. et al.

mesylate treatment: a potential diagnostic pitfall. *Histopathology, 47,* 41-47. Prakash, S., Sarran, L., Socci, N., Dematteo, R. P., Eisenstat, J., Greco, A. M. et al. (2005).

Pruneri, G., Mazzarol, G., Fabris, S., Del Curto, B., Bertolini, F., Neri, A. et al. (2003). Cyclin

Reith, J. D., Goldblum, J. R., Lyles, R. H., & Weiss, S. W. (2000). Extragastrointestinal (soft

Ricci, R., Arena, V., Castri, F., Martini, M., Maggiano, N., Murazio, M. et al. (2004). Role of

Rossi, G., Valli, R., Bertolini, F., Marchioni, A., Cavazza, A., Mucciarini, C. et al. (2005).

Rubin, B. P. (2006). Gastrointestinal stromal tumours: an update. *Histopathology, 48,* 83-96. Rubin, B. P., Fletcher, J. A., & Fletcher, C. D. (2000). Molecular Insights into the Histogenesis and Pathogenesis of Gastrointestinal Stromal Tumors. *Int.J.Surg.Pathol., 8,* 5-10. Rubin, B. P., Singer, S., Tsao, C., Duensing, A., Lux, M. L., Ruiz, R. et al. (2001). KIT

Rudolph, P., Gloeckner, K., Parwaresch, R., Harms, D., & Schmidt, D. (1998).

tumors: a contemporary review. *Pathol.Res.Pract., 202,* 837-847.

*J.Pediatr.Hematol.Oncol., 27,* 179-187.

predictors of outcome. *Mod.Pathol., 13,* 577-585.

*Mod.Pathol., 16,* 886-892.

*Histopathology, 46,* 522-531.

*Hum.Pathol., 29,* 791-800.

43.

8118-8121.

Different inhibitory effect of imatinib on phosphorylation of mitogen-activated protein kinase and Akt and on proliferation in cells expressing different types of mutant platelet-derived growth factor receptor-alpha. *Int.J.Cancer, 111,* 317-321. Panizo-Santos, A., Sola, I., Vega, F., de Alava, E., Lozano, M. D., Idoate, M. A. et al. (2000).

Predicting Metastatic Risk of Gastrointestinal Stromal Tumors: Role of Cell Proliferation and Cell Cycle Regulatory Proteins. *Int.J.Surg.Pathol., 8,* 133-144. Parfitt, J. R., Streutker, C. J., Riddell, R. H., & Driman, D. K. (2006). Gastrointestinal stromal

(2008). Clinical and molecular genetics of patients with the Carney-Stratakis syndrome and germline mutations of the genes coding for the succinate dehydrogenase subunits SDHB, SDHC, and SDHD. *Eur.J.Hum.Genet., 16,* 79-88. Pauwels, P., Debiec-Rychter, M., Stul, M., De Wever, I., van Oosterom, A. T., & Sciot, R.

(2005). Changing phenotype of gastrointestinal stromal tumours under imatinib

Gastrointestinal stromal tumors in children and young adults: a clinicopathologic, molecular, and genomic study of 15 cases and review of the literature.

D3 immunoreactivity in gastrointestinal stromal tumors is independent of cyclin D3 gene amplification and is associated with nuclear p27 accumulation.

tissue) stromal tumors: an analysis of 48 cases with emphasis on histologic

p16/INK4a in gastrointestinal stromal tumor progression. *Am.J.Clin.Pathol., 122,* 35-

PDGFR expression in differential diagnosis between KIT-negative gastrointestinal stromal tumours and other primary soft-tissue tumours of the gastrointestinal tract.

activation is a ubiquitous feature of gastrointestinal stromal tumors. *Cancer Res., 61,*

Immunophenotype, proliferation, DNA ploidy, and biological behavior of gastrointestinal stromal tumors: a multivariate clinicopathologic study.

separated from gastrointestinal stromal tumors-a clinicopathologic and immunohistochemical study of eighty-eight cases. *Mod.Pathol., 14,* 950-956.


immunohistochemical study of eighty-eight cases. *Mod.Pathol., 14,* 950-956. Miettinen, M., Sarlomo-Rikala, M., Sobin, L. H., & Lasota, J. (2000a). Esophageal stromal

Miettinen, M. & Sobin, L. H. (2001). Gastrointestinal stromal tumors in the appendix: a

Miettinen, M., Sobin, L. H., & Lasota, J. (2005). Gastrointestinal stromal tumors of the

Miettinen, M., Sobin, L. H., & Sarlomo-Rikala, M. (2000b). Immunohistochemical spectrum

Miettinen, M., Virolainen, M., & Maarit, S. R. (1995). Gastrointestinal stromal tumors--value

Montemurro, M., Schoffski, P., Reichardt, P., Gelderblom, H., Schutte, J., Hartmann, J. T. et

Montgomery, E., Torbenson, M. S., Kaushal, M., Fisher, C., & Abraham, S. C. (2002). Beta-

Motegi, A., Sakurai, S., Nakayama, H., Sano, T., Oyama, T., & Nakajima, T. (2005). PKC

Nemoto, Y., Mikami, T., Hana, K., Kikuchi, S., Kobayashi, N., Watanabe, M. et al. (2006).

Nilsson, B., Bumming, P., Meis-Kindblom, J. M., Oden, A., Dortok, A., Gustavsson, B. et al.

Nishida, T., Hirota, S., Taniguchi, M., Hashimoto, K., Isozaki, K., Nakamura, H. et al. (1998).

O'Brien, P., Kapusta, L., Dardick, I., Axler, J., & Gnidec, A. (1999). Multiple familial

O'Leary, T., Ernst, S., Przygodzki, R., Emory, T., & Sobin, L. (1999). Loss of heterozygosity at

resistant to both imatinib and sunitinib. *Eur.J.Cancer, 45,* 2293-2297.

of 1765 cases with long-term follow-up. *Am.J.Surg.Pathol., 29,* 52-68.

*Am.J.Surg.Pathol., 24,* 211-222.

(KIT). *Mod.Pathol., 13,* 1134-1142.

schwannomas. *Am.J.Surg Pathol, 19,* 207-216.

western Sweden. *Cancer, 103,* 821-829.

*Nat.Genet., 19,* 323-324.

*Am.J.Surg Pathol, 23,* 198-204.

*Lab Invest, 79,* 1461-1467.

*25,* 1433-1437.

1296-1301.

112.

separated from gastrointestinal stromal tumors-a clinicopathologic and

tumors: a clinicopathologic, immunohistochemical, and molecular genetic study of 17 cases and comparison with esophageal leiomyomas and leiomyosarcomas.

clinicopathologic and immunohistochemical study of four cases. *Am.J.Surg.Pathol.,* 

stomach: a clinicopathologic, immunohistochemical, and molecular genetic study

of GISTs at different sites and their differential diagnosis with a reference to CD117

of CD34 antigen in their identification and separation from true leiomyomas and

al. (2009). Nilotinib in the treatment of advanced gastrointestinal stromal tumours

catenin immunohistochemistry separates mesenteric fibromatosis from gastrointestinal stromal tumor and sclerosing mesenteritis. *Am.J.Surg.Pathol., 26,*

theta, a novel immunohistochemical marker for gastrointestinal stromal tumors (GIST), especially useful for identifying KIT-negative tumors. *Pathol.Int., 55,* 106-

Correlation of enhanced cell turnover with prognosis of gastrointestinal stromal tumors of the stomach: relevance of cellularity and p27kip1. *Pathol.Int., 56,* 724-731.

(2005). Gastrointestinal stromal tumors: the incidence, prevalence, clinical course, and prognostication in the preimatinib mesylate era--a population-based study in

Familial gastrointestinal stromal tumours with germline mutation of the KIT gene.

gastrointestinal autonomic nerve tumors and small intestinal neuronal dysplasia.

1p36 predicts poor prognosis in gastrointestinal stromal/smooth muscle tumors.


Gastrointestinal Stromal Tumours:

*39,* 2012-2020.

2628.

*106,* 887-895.

107-113.

disease). *Am.J.Surg.Pathol., 29,* 755-763.

observations. *Int.J.Gynecol.Pathol., 1,* 59-74.

stromal tumours. *J.Clin.Pathol., 59,* 557-563.

stromal tumours: a phase I study. *Lancet, 358,* 1421-1423.

ligand in human disease. *J.Allergy Clin.Immunol., 100,* 435-440.

23 cases. *Br.J.Cancer, 85,* 405-411.

*Am.J.Gastroenterol., 100,* 162-168.

(GIST). *Jpn.J.Clin.Oncol., 32,* 347-351.

stomach. *Histopathology, 43,* 118-126.

A Contemporary Review on Pathogenesis, Morphology and Prognosis 205

Stroobants, S., Goeminne, J., Seegers, M., Dimitrijevic, S., Dupont, P., Nuyts, J. et al. (2003).

Takazawa, Y., Sakurai, S., Sakuma, Y., Ikeda, T., Yamaguchi, J., Hashizume, Y. et al. (2005).

Tamborini, E., Papini, D., Mezzelani, A., Riva, C., Azzarelli, A., Sozzi, G. et al. (2001). c-KIT

Tavassoli, F. A. & Norris, H. J. (1982). Peritoneal leiomyomatosis (leiomyomatosis

Tornillo, L. & Terracciano, L. M. (2006). An update on molecular genetics of gastrointestinal

Tran, T., Davila, J. A., & El-Serag, H. B. (2005). The epidemiology of malignant

van Oosterom, A. T., Judson, I., Verweij, J., Stroobants, S., Donato di Paola, E., Dimitrijevic,

Vliagoftis, H., Worobec, A. S., & Metcalfe, D. D. (1997). The protooncogene c-kit and c-kit

Wang, Q. & Kou, Y. W. (2007). Study of the expressions of p53 and bcl-2 genes, the

Wang, X., Mori, I., Tang, W., Utsunomiya, H., Nakamura, M., Nakamura, Y. et al. (2002).

Wardelmann, E., Losen, I., Hans, V., Neidt, I., Speidel, N., Bierhoff, E. et al. (2003). Deletion

West, R. B., Corless, C. L., Chen, X., Rubin, B. P., Subramanian, S., Montgomery, K. et al.

Willmore, C., Holden, J. A., Zhou, L., Tripp, S., Wittwer, C. T., & Layfield, L. J. (2004).

resolution amplicon melting analysis. *Am.J.Clin.Pathol., 122,* 206-216. Wong, N. A., Young, R., Malcomson, R. D., Nayar, A. G., Jamieson, L. A., Save, V. E. et al.

18FDG-Positron emission tomography for the early prediction of response in advanced soft tissue sarcoma treated with imatinib mesylate (Glivec). *Eur.J.Cancer,* 

Gastrointestinal stromal tumors of neurofibromatosis type I (von Recklinghausen's

and c-KIT ligand (SCF) in synovial sarcoma (SS): an mRNA expression analysis in

peritonealis disseminata): a clinicopathologic study of 20 cases with ultrastructural

gastrointestinal stromal tumors: an analysis of 1,458 cases from 1992 to 2000.

S. et al. (2001). Safety and efficacy of imatinib (STI571) in metastatic gastrointestinal

telomerase activity and apoptosis in GIST patients. *World J.Gastroenterol., 13,* 2626-

Helpful parameter for malignant potential of gastrointestinal stromal tumors

of Trp-557 and Lys-558 in the juxtamembrane domain of the c-kit protooncogene is associated with metastatic behavior of gastrointestinal stromal tumors. *Int.J.Cancer,* 

(2004). The novel marker, DOG1, is expressed ubiquitously in gastrointestinal stromal tumors irrespective of KIT or PDGFRA mutation status. *Am.J.Pathol., 165,*

Detection of c-kit-activating mutations in gastrointestinal stromal tumors by high-

(2003). Prognostic indicators for gastrointestinal stromal tumours: a clinicopathological and immunohistochemical study of 108 resected cases of the

Stout AP (1976). Bizarre smooth muscle tumours of the stomach. *Cancer, 15,* 400-409.


Ryu, M. H., Kang, Y. K., Jang, S. J., Kim, T. W., Lee, H., Kim, J. S. et al. (2007). Prognostic

Sabah, M., Cummins, R., Leader, M., & Kay, E. (2004a). Expression of human telomerase

Sabah, M., Cummins, R., Leader, M., & Kay, E. (2004b). Loss of heterozygosity of

Sabah, M., Cummins, R., Leader, M., & Kay, E. (2006). Altered expression of cell cycle

Sabah, M., Leader, M., & Kay, E. (2003). The problem with KIT: clinical implications and

Sakurai, S., Fukayama, M., Kaizaki, Y., Saito, K., Kanazawa, K., Kitamura, M. et al. (1998). Telomerase activity in gastrointestinal stromal tumors. *Cancer, 83,* 2060-2066. Sakurai, S., Oguni, S., Hironaka, M., Fukayama, M., Morinaga, S., & Saito, K. (2001).

Sandberg, A. A. & Bridge, J. A. (2002). Updates on the cytogenetics and molecular genetics

Sarlomo-Rikala, M., El Rifai, W., Lahtinen, T., Andersson, L. C., Miettinen, M., & Knuutila, S.

Schneider-Stock, R., Boltze, C., Lasota, J., Miettinen, M., Peters, B., Pross, M. et al. (2003).

Schneider-Stock, R., Boltze, C., Lasota, J., Peters, B., Corless, C. L., Ruemmele, P. et al. (2005).

Sciot, R. & Debiec-Rychter, M. (2006). GIST under imatinib therapy. *Semin.Diagn.Pathol., 23,*

Segal, A., Carello, S., Caterina, P., Papadimitriou, J. M., & Spagnolo, D. V. (1994).

Singer, S., Rubin, B. P., Lux, M. L., Chen, C. J., Demetri, G. D., Fletcher, C. D. et al. (2002).

Steigen, S. E., Bjerkehagen, B., Haugland, H. K., Nordrum, I. S., Loberg, E. M., Isaksen, V. et

causing specific inhibition of cyclin D/CDK4. *Nature, 366,* 704-707.

gastrointestinal stromal tumors. *J.Clin.Oncol., 20,* 3898-3905.

tumors, leiomyomas, and schwannomas. *Hum.Pathol, 29,* 476-481.

a tissue microarray study. *Clin.Cancer Res., 11,* 638-645.

gastrointestinal stromal tumours. *Histopathology, 51,* 379-389.

malignant neoplasms. *Hum.Pathol., 35,* 1231-1235.

prognostic implications. *Hum.Pathol., 37,* 648-655.

practical difficulties with CD117 immunostaining. *Appl.Immunohistochem.Mol.Morphol., 11,* 56-61.

Japanese. *Jpn.J.Cancer Res., 92,* 494-498.

*Genet.Cytogenet., 135,* 1-22.

*J.Clin.Oncol., 21,* 1688-1697.

Norway. *Mod.Pathol., 21,* 46-53.

84-90.

Sakamoto, K. M. (2004). Su-11248 Sugen. *Curr.Opin.Investig.Drugs, 5,* 1329-1339.

gastrointestinal stromal tumors. *Mod.Pathol.*.

significance of p53 gene mutations and protein overexpression in localized

reverse transcriptase in gastrointestinal stromal tumors occurs preferentially in

chromosome 9p and loss of p16(INK4A) expression are associated with malignant

regulatory proteins in gastrointestinal stromal tumors: markers with potential

Mutations in c-kit gene exons 9 and 13 in gastrointestinal stromal tumors among

of bone and soft tissue tumors. Gastrointestinal stromal tumors. *Cancer* 

(1998). Different patterns of DNA copy number changes in gastrointestinal stromal

High prognostic value of p16INK4 alterations in gastrointestinal stromal tumors.

Loss of p16 protein defines high-risk patients with gastrointestinal stromal tumors:

Gastrointestinal autonomic nerve tumors: a clinicopathological, immunohistochemical and ultrastructural study of 10 cases. *Pathology, 26,* 439-447. Serrano, M., Hannon, G. J., & Beach, D. (1993). A new regulatory motif in cell-cycle control

Prognostic value of KIT mutation type, mitotic activity, and histologic subtype in

al. (2008). Diagnostic and prognostic markers for gastrointestinal stromal tumors in

Stout AP (1976). Bizarre smooth muscle tumours of the stomach. *Cancer, 15,* 400-409.


**Part 4** 

**Treatment of Soft Tissue Tumors** 


**Part 4** 

**Treatment of Soft Tissue Tumors** 

206 Soft Tissue Tumors

Wozniak, A., Sciot, R., Guillou, L., Pauwels, P., Wasag, B., Stul, M. et al. (2007). Array CGH

Yalcinkaya, U., Yerci, O., & Koc, E. U. (2007). Significance of p53 expression in

Yantiss, R. K., Rosenberg, A. E., Sarran, L., Besmer, P., & Antonescu, C. R. (2005). Multiple

Yantiss, R. K., Spiro, I. J., Compton, C. C., & Rosenberg, A. E. (2000). Gastrointestinal stromal

gastrointestinal stromal tumors. *Hepatogastroenterology, 54,* 140-143.

*Genes Chromosomes.Cancer, 46,* 261-276.

molecular study. *Mod.Pathol., 18,* 475-484.

differential diagnosis. *Am.J.Surg.Pathol., 24,* 947-957.

analysis in primary gastrointestinal stromal tumors: cytogenetic profile correlates with anatomic site and tumor aggressiveness, irrespective of mutational status.

gastrointestinal stromal tumors in type I neurofibromatosis: a pathologic and

tumor versus intra-abdominal fibromatosis of the bowel wall: a clinically important

**11** 

*Russia* 

**Treatment of Synovial Sarcoma in Children** 

Karseladze Appolon Irodionovich2 and Ivanova Nadezhda Mikhailovna1

A synovial sarcoma (SS) is a rare soft tissue sarcoma; in children and adolescents it accounts for 4 % of all non-rhabdomyosarcoma soft tissue sarcomas. The most common site of primary disease is the lower limbs. Although relatively rare, SS is the third most common extremity STS. In both children and adults three histopathologic subtypes of SS are described (monophasic, biphasic and poorly differentiated); it is associated with a characteristic translocation t(x;18) [23;17]. Despite considerable progress and achievements in child oncology, treating children with synovial sarcoma still remains a pressing problem. Numerous treatment options available today to children with SS and dispute among

Herein, we analyze the outcomes in 48 patients with various localizations of synovial sarcoma who were treated in N. N. Blokhin Cancer Research Centre between 1990 and 2007. The results were evaluated on 31 December 2010. The analyzed group was divided into two subgroups – the control group (historical control group) and the study group (experimental group) – matched for sex, age, localization of cancer, extent of tumor spread and recurrence. The mean age in the historical control group (1990-1999) was 10.41±4.03 years (range, 1.0 to 15.0 years). The group included 29 pediatric patients – 13 males (44.8 %), 16 females (55.2%). 20 (69.9%) test subjects were diagnosed with biphasic synovial sarcoma, 8 (27.6%) – with monophasic subtype and 1 (3.4%) – with poorly differentiated subtype. In all cases the diagnosis was based upon morphological study. Immunohistochemistry was used in 14 (48.2%) cases to verify the diagnosis. The most likely localization of lesions was the lower extremity – 14 (48.3%) cases. 10 (34.5%) patients had lesions in upper extremities and 4 (13.8%) in the trunk. One patient was diagnosed with retroperitoneal synovial sarcoma. Mean tumor volume in the control group was 49.1 cm3. 22 patients (75.9 %) had tumor size

researchers show high importance of the issue and necessity of its complex study.

**1. Introduction** 

**2. Materials and methods** 

above 5 cm.

Shvarova Anna Viktorovna1, Rykov Maxim Yurjevich1,

*N. N. Blokhin Cancer Research Center, Department of Surgery №3* 

 *2Institute of Clinical Oncology N. N. Blokhin Cancer Research Centre,* 

*1Institute of Paediatric Oncology and Hematology,* 

*(The Musculo-Sceletal Tumors Department), Moscow,* 

*Department of Human Tumor Pathologic Anatomy, Moscow* 
