Contemporary Pathology of Gastrointestinal Stromal Tumors

https://doi.org/10.1016/j.hoc.2008.12.002Get rights and content

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. The vast majority of GISTs harbor a KIT or PDGFRA mutation and express KIT by immunohistochemistry. However, KIT-negative tumors and tumors showing unusual morphologic features can cause major diagnostic problems. The ability to inhibit the active KIT or PDGFRA kinase with tyrosine kinase inhibitors and alternative drugs demands more than ever accurate tumor classification and risk assessment. This article focuses on the pathology of GIST, including unusual variants and morphologic changes resulting from treatment. Parameters for risk assessment, potentially helpful new immunohistochemical markers, differential diagnosis, and the application of molecular classification schemes are discussed.

Section snippets

Epidemiology

The incidence of GIST in the United States and Europe is difficult to determine because GISTs have been recognized and uniformly diagnosed as a discrete entity only since the late 1990s. Recent population-based studies in some European countries found an incidence between 11 and 14.5 cases per million.14, 15, 16 These findings would translate into an annual incidence in the United States of 4,000 to 5,000 cases. However, the prevalence of GIST may be even higher, as many patients live with the

Clinical Features

The majority of patients diagnosed with GISTs are between 40 and 80 years of age (median age approximately 60 years).22 There is no clear sex predilection. Rarely, GISTs occur in children; pediatric GISTs are considered a separate clinicopathologic entity, occurring predominantly in the second decade.23, 24 Most GISTs are sporadic, but familial GISTs associated with inherited germline mutations have been identified.25, 26, 27, 28, 29, 30, 31 GISTs have also been demonstrated in association with

Immunohistochemical markers and PCR-based assays in the diagnosis of Gastrointestinal Stromal Tumors

KIT has been demonstrated as a very specific and sensitive marker in the differential diagnosis of mesenchymal tumors in the GI tract;48 around 95% of GISTs express KIT.5, 6, 49, 50 Different KIT staining patterns can be seen. Most GISTs show strong and diffuse cytoplasmic staining, whereas nearly half show concurrent dot-like (Golgi-pattern) staining (Fig. 5 A and B). In a minority of cases, a purely dot-like (see Fig. 2B) or even a membranous staining pattern can be observed. The extent and

Risk assessment in Gastrointestinal Stromal Tumors

Morphologic risk assessment in GISTs provides the basis for clinical management and optimal patient care. The vast majority of studies of GISTs suggest that the two most important prognostic features to assess the risk of aggressive behavior in a primary GIST are mitotic activity and tumor size. These two features were the foundation of the consensus approach for risk assessment in GISTs published by Fletcher and colleagues1, 68 in 2002 (Table 1). Subsequent data collected by Miettinen and

Proposed prognostically valuable immunohistochemical markers in Gastrointestinal Stromal Tumors

The tumor suppressor gene CDKN2A (p16) on chromosome 9p21 is an important cell cycle inhibitor that has been shown to be inactivated in a significant proportion of malignancies.72, 73, 74, 75, 76, 77 Immunohistochemistry has been used to assess p16 status, and the down-regulation of p16 correlates with aggressive behavior in GISTs, apparently even in tumors that are classified as low risk according to standard morphologic parameters.73, 74, 76

Another cell cycle inhibitor, p27, has been shown to

Differential diagnosis

The main differential diagnostic considerations for spindle cell GISTs are smooth muscle tumors, desmoid fibromatosis, schwannoma, inflammatory myofibroblastic tumor, inflammatory fibroid polyp, solitary fibrous tumor, and synovial sarcoma (Fig. 8). Importantly, all of these tumor types are consistently negative for KIT. Mural leiomyomas occur most commonly in the esophagus, and at this location are more common than GISTs, with a 3-to-1 ratio.83 In contrast to the syncytial appearance of

Molecular classification of Gastrointestinal Stromal Tumors

Objective clinical response to imatinib has been shown to depend on the type of RTK mutation, and a molecular classification of GISTs has been proposed.95, 96 Based on the results of clinical trials (phase I–III)12 investigating over 700 genotyped GISTs,11, 97, 98 the objective response rate for KIT exon 11 mutant GISTs is 72% to 86%, compared with 38% to 48% for KIT exon 9 mutations, and up to 28% for wild-type GISTs.11, 97, 98, 99 Primary resistance to imatinib has been likewise demonstrated

Summary

There is a wide morphologic spectrum of GISTs, but virtually all cases are amenable to the proposed primary parameters for risk assessment (size, mitotic index, and anatomic site). In addition to the common morphologic subgroups of GIST (spindle cell, epithelioid, and mixed), unusual morphologic variants, morphologic changes after TKI treatment, and treatment effects on GISTs are encountered. Promising new immunohistochemical markers (such as DOG1.1) will likely be diagnostically valuable,

Acknowledgments

The authors thank Kim Vu for expert assistance in figure production and Lindsey P. Lyle for gross photography. The authors also thank Dr. Chris Corless of Oregon Health and Science University, Portland, Oregon for the adapted and corrected 2007 NCCN risk assessment chart.

References (102)

  • J.D. Reith et al.

    Extragastrointestinal (soft tissue) stromal tumors: an analysis of 48 cases with emphasis on histologic predictors of outcome

    Mod Pathol

    (2000)
  • T. de Raedt et al.

    Intestinal neurofibromatosis is a subtype of familial GIST and results from a dominant activating mutation in PDGFRA

    Gastroenterology

    (2006)
  • E. Weisberg et al.

    Effects of PKC412, nilotinib, and imatinib against GIST-associated PDGFRA mutants with differential imatinib sensitivity

    Gastroenterology

    (2006)
  • R.B. West et al.

    The novel marker, DOG1, is expressed ubiquitously in gastrointestinal stromal tumors irrespective of KIT or PDGFRA mutation status

    Am J Pathol

    (2004)
  • M. Miettinen et al.

    Gastrointestinal stromal tumors: pathology and prognosis at different sites

    Semin Diagn Pathol

    (2006)
  • M. Sabah et al.

    Loss of heterozygosity of chromosome 9p and loss of p16INK4A expression are associated with malignant gastrointestinal stromal tumors

    Mod Pathol

    (2004)
  • S.E. Steigen et al.

    Diagnostic and prognostic markers for gastrointestinal stromal tumors in Norway

    Mod Pathol

    (2008)
  • G. Pruneri et al.

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

    Mod Pathol

    (2003)
  • L. Tornillo et al.

    Patterns of gene amplification in gastrointestinal stromal tumors (GIST)

    Lab Invest

    (2005)
  • M.H. Cessna et al.

    Expression of ALK1 and p80 in inflammatory myofibroblastic tumor and its mesenchymal mimics: a study of 135 cases

    Mod Pathol

    (2002)
  • M. Debiec-Rychter et al.

    KIT mutations and dose selection for imatinib in patients with advanced gastrointestinal stromal tumours

    Eur J Cancer

    (2006)
  • S. Hirota et al.

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

    Gastroenterology

    (2003)
  • M.T. Mazur et al.

    Gastric stromal tumors. Reappraisal of histogenesis

    Am J Surg Pathol

    (1983)
  • M. Miettinen et al.

    Gastrointestinal stromal tumors—value of CD34 antigen in their identification and separation from true leiomyomas and schwannomas

    Am J Surg Pathol

    (1995)
  • J.D. Huizinga et al.

    W/kit gene required for interstitial cells of Cajal and for intestinal pacemaker activity

    Nature

    (1995)
  • S. Hirota et al.

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

    Science

    (1998)
  • L. Kindblom et al.

    Gastrointestinal pacemaker cell tumor (GIPACT): gastrointestinal stromal tumors show phenotypic characteristics of the interstitial cells of Cajal

    Am J Pathol

    (1998)
  • M.C. Heinrich et al.

    PDGFRA activating mutations in gastrointestinal stromal tumors

    Science

    (2003)
  • M.C. Heinrich et al.

    Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor

    J Clin Oncol

    (2003)
  • G.D. Demetri et al.

    NCCN Task Force report: management of patients with gastrointestinal stromal tumor (GIST)–update of the NCCN clinical practice guidelines

    J Natl Compr Canc Netw

    (2007)
  • J.H. Edmonson et al.

    Contrast of response to dacarbazine, mitomycin, doxorubicin, and cisplatin (DMAP) plus GM-CSF between patients with advanced malignant gastrointestinal stromal tumors and patients with other advanced leiomyosarcomas

    Cancer Invest

    (2002)
  • B. Nilsson et al.

    Gastrointestinal stromal tumors: the incidence, prevalence, clinical course, and prognostication in the preimatinib mesylate era—a population-based study in western Sweden

    Cancer

    (2005)
  • G. Tryggvason et al.

    Gastrointestinal stromal tumors in Iceland, 1990–2003: the Icelandic GIST study, a population-based incidence and pathologic risk stratification study

    Int J Cancer

    (2005)
  • A. Agaimy et al.

    Minute gastric sclerosing stromal tumors (GIST tumorlets) are common in adults and frequently show c-KIT mutations

    Am J Surg Pathol

    (2007)
  • S.C. Abraham et al.

    “Seedling” mesenchymal tumors (gastrointestinal stromal tumors and leiomyomas) are common incidental tumors of the esophagogastric junction

    Am J Surg Pathol

    (2007)
  • A. Agaimy et al.

    Microscopic gastrointestinal stromal tumors in esophageal and intestinal surgical resection specimens: a clinicopathologic, immunohistochemical, and molecular study of 19 lesions

    Am J Surg Pathol

    (2008)
  • M. Miettinen et al.

    Gastrointestinal stromal tumors of the stomach: a clinicopathologic, immunohistochemical, and molecular genetic study of 1765 cases with long-term follow-up

    Am J Surg Pathol

    (2005)
  • S. Prakash et al.

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

    J Pediatr Hematol Oncol

    (2005)
  • K.A. Janeway et al.

    Pediatric KIT wild-type and platelet-derived growth factor receptor alpha- wild-type gastrointestinal stromal tumors share KIT activation but not mechanisms of genetic progression with adult gastrointestinal stromal tumors

    Cancer Res

    (2007)
  • A. Beghini et al.

    Germline mutation in the juxtamembrane domain of the kit gene in a family with gastrointestinal stromal tumors and urticaria pigmentosa

    Cancer

    (2001)
  • D.Y. Kang et al.

    Multiple gastrointestinal stromal tumors: Clinicopathologic and genetic analysis of 12 patients

    Am J Surg Pathol

    (2007)
  • T. Nishida et al.

    Familial gastrointestinal stromal tumours with germline mutation of the KIT gene

    Nat Genet

    (1998)
  • C. O'Riain et al.

    Gastrointestinal stromal tumors: insights from a new familial GIST kindred with unusual genetic and pathologic features

    Am J Surg Pathol

    (2005)
  • E.P. Kleinbaum et al.

    Clinical, histopathologic, molecular and therapeutic findings in a large kindred with gastrointestinal stromal tumor

    Int J Cancer

    (2008)
  • J. Andersson et al.

    NF1-associated gastrointestinal stromal tumors have unique clinical, phenotypic, and genotypic characteristics

    Am J Surg Pathol

    (2005)
  • O. Maertens et al.

    Molecular pathogenesis of multiple gastrointestinal stromal tumors in NF1 patients

    Hum Mol Genet

    (2006)
  • M. Miettinen et al.

    Gastrointestinal stromal tumors in patients with neurofibromatosis 1: a clinicopathologic and molecular genetic study of 45 cases

    Am J Surg Pathol

    (2006)
  • J.A. Carney et al.

    Familial paraganglioma and gastric stromal sarcoma: a new syndrome distinct from the Carney triad

    Am J Med Genet

    (2002)
  • B. Pasini et al.

    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

    (2008)
  • R.P. DeMatteo et al.

    Two hundred gastrointestinal stromal tumors: recurrence patterns and prognostic factors for survival

    Ann Surg

    (2000)
  • Cited by (27)

    • Assessment of metastatic risk of gastric GIST based on treatment-naïve CT features

      2016, European Journal of Surgical Oncology
      Citation Excerpt :

      Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumor of the gastrointestinal tract.1,2 Within the gastrointestinal tract, GIST occurs most frequently in the stomach (40–60%) followed by the small intestine (25–35%), colorectum (5–15%) and esophagus (<1%).3–6 Risk stratification of GIST is currently based on size, mitotic count and tumor location.

    • Resistance to treatment in gastrointestinal stromal tumours: What radiologists should know

      2013, Clinical Radiology
      Citation Excerpt :

      Gastrointestinal stromal tumours (GISTs) constitute less than 1% of all GI tumours, but with an annual incidence of 15 cases per million in the UK, GISTs are still the most common mesenchymal tumours of the GI tract.1 Considered to be smooth muscle tumours until the 1990s, GISTs are now known to be derived from interstitial cells of Cajal (the pacemaker cells of the GI tract) or their precursors.2 The characteristic feature in the pathogenesis of GISTs is the presence of activating mutations of the gene encoding the receptor tyrosine kinase (RTK) KIT.

    • Exon 11 mutations, Ki67, and p16<sup>INK4A</sup> as predictors of prognosis in patients with GIST

      2011, Pathology Research and Practice
      Citation Excerpt :

      Macroscopically, GISTs are non-encapsulated, well-defined, intra-abdominal nodular lesions, which can cause a bulging in the lumen of the gastrointestinal tract [22,35]. On histology, about 70% of GISTs are composed of spindle-cells, 20% of epithelioid cells, and the remaining 10% of mixed cell types [10,22,27]. The tyrosine-kinase receptor CD117 (KIT) is present in 90–95% of GISTs, usually with diffuse cytoplasmic expression [16,28].

    View all citing articles on Scopus

    This work supported in part by the University of Texas M.D. Anderson Cancer Center Physician Scientist Program (A.J.L.). B.L. was supported by the FWF Austrian Science Fund.

    View full text