Pathology (February 2014) 46(2), pp. 141–148
SOFT TISSUE PATHOLOGY
The changing face of GIST: implications for pathologists CHRIS HEMMINGS1,2
AND
DESMOND YIP3,4
1St John of God Pathology Subiaco, 2School of Surgery, University of Western Australia, Western Australia, 3Department of Medical Oncology, The Canberra Hospital, and 4ANU Medical School, Australian National
University, Canberra, Australian Capital Territory, Australia
Summary Gastrointestinal stromal tumour (GIST) is now recognised as the most common primary mesenchymal tumour of the gut. A number of different parameters have been identified to aid prediction of clinical behaviour, but prognostication for an individual remains difficult. The pathologist plays a crucial role in guiding management of these tumours, but is faced with a number of challenges in so doing. This review describes the variable pathological features that may be encountered, and examines some of the issues in the pathology reporting of GIST and attempts to provide some guidance in factors that should be addressed in a comprehensive pathology report. Key words: Gastrointestinal stromal tumour, histopathology, immunohistochemistry, KIT, mutational analysis, PDGFRA, risk stratification, SDHB, SDHB. Received 5 September, revised and accepted 15 September 2013
INTRODUCTION Gastrointestinal stromal tumour (GIST) is now recognised as the most common primary mesenchymal tumour of the gut, having an annual incidence of around 11–15 per 100,000 (based on Scandinavian population-based studies).1 If incidental microscopic GISTs (for example, found at surgery for gastric or oesophageal cancer or at autopsy) are included, the frequency is much greater; perhaps 1 in 10 or more. (It has been suggested that up to 20% of the population may harbour micro-GIST, although only a small fraction of these will develop clinically significant tumours.2,3) Since GIST became recognised towards the end of last century, there has been an expansion in our understanding of not only the biology of this fascinating tumour, but of the spectrum of histological appearances and clinical features that it may show. Histologically similar tumours span a clinical spectrum from benign to aggressively malignant, and this has lead to a number of attempts4–11 to better identify pathological features (both morphological and molecular) that may predict subsequent behaviour, or suggest a specific clinical syndrome. Nonetheless, predicting how a particular patient’s tumour will behave remains imperfect, and the pathologist is faced with a bewildering array of options when formulating a report. This review examines some of the issues in the pathology reporting of GIST and attempts to provide some guidance as to factors that should be addressed.
CLINICAL FEATURES More than half of all GIST occur in the stomach and about another third in the small intestine (particularly the jejunum and Print ISSN 0031-3025/Online ISSN 1465-3931 DOI: 10.1097/PAT.0000000000000047
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ileum), around 5% in the colorectum and only about 1% in the oesophagus, where leiomyoma is the most common mesenchymal tumour. Despite initial debate about their true origin (metastasis from an occult intestinal primary or ‘decapitated’ extension from a mural tumour versus truly extraintestinal origin),12 uncommon cases of extraintestinal GIST (arising within mesentery or omentum) are now generally accepted to occur, and at least one credible example of primary GIST arising outside the abdomen has been reported.13 Non-syndromic GIST typically occurs in older adults (median age around 60 years),1 with perhaps a slight male preponderance, whereas syndromic GIST tends to occur at a younger age and, in the case of SDH-deficient GIST, more commonly in females. The most common clinical presentations include gastrointestinal bleeding, vague abdominal complaints and incidental findings. Gastric outlet obstruction is rare1 but small intestinal tumours may cause obstruction with or without intussusception. Malignant GISTs typically disseminate by coelomic spread within the abdomen and/or metastasis to the liver, and less frequently to other organs such as ovary.14 Extra-abdominal metastasis is extremely unusual, but has been reported.15–17 Syndromes and associations Most GISTs arise sporadically, but they may also occur in association with a number of clinical syndromes, which may only be recognised when the patient presents with GIST. These include Carney triad (GIST, pulmonary chondroma and paraganglioma), Carney–Stratakis syndrome (GIST and paraganglioma), familial GIST syndrome and neurofibromatosis type 1 (NF1). Carney triad was first described in 197718 and is thought to be non-hereditary. GISTs occurring in Carney triad tend to arise in the gastric antrum of females and display epithelioid morphology, and typically present at a younger age than sporadic GISTs (including in children). The existence of a syndrome of familial paraganglioma and GIST, different from the previously described Carney triad, was proposed in 200219 and has subsequently become known as Carney–Stratakis syndrome. This syndrome is inherited in an autosomal dominant fashion but with incomplete penetrance, and displays a variable clinical phenotype. The underlying molecular pathogenesis was subsequently found to be any of several germline mutations in the genes encoding one or other subunit of succinate dehydrogenase (SDH),20–22 an enzyme involved in cellular respiration but also thought to function as a tumour suppressor.23 (By comparison, subsequent analysis of tumours associated with Carney triad found no coding sequence mutations in SDH genes, although copy number changes were
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seen.24) Functional loss of the SDH complex can be identified immunohistochemically by loss of expression of SDH subunits,21,25–27 and this will be observed in a significant proportion of all gastric GISTs occurring under the age of 40, including nearly all of those under 20 years. There is a preponderance of female patients of over 2:1 in this group.25 Overall, perhaps 5% of all GISTs are SDH-deficient, although only around half of these harbour SDH mutations; this includes a small subset of apparently sporadic GISTs arising in adults, as well as the vast majority of GISTs arising in children, and those associated with either Carney–Stratakis syndrome or Carney triad (J. Hornick, personal communication). The rare familial GIST syndrome is associated with various germline mutations in KIT or PDGFRA, usually inherited in an autosomal dominant manner. These patients tend to develop multiple lesions throughout the gastrointestinal tract, often from a young age, and typically display cutaneous hyperpigmentation, which may predate the development of GIST.23,28–31 Patients with NF1 are at increased risk of developing GIST, which most commonly arise in the small intestine and are often multifocal and associated with diffuse ICC (Interstitial Cell of Cajal) hyperplasia.32 These tumours usually have spindle cell morphology with infrequent mitoses and may lack KIT (CD117) positivity,5 but CD34 and DOG-1 are usually expressed. Despite the finding that haemorrhage and necrosis (normally worrisome features) are relatively common, clinical behaviour tends to be indolent, but when treated, primary imatinib resistance is common.33 Although typically wild-type for both KIT and PDGFRA mutations, NF1-associated GISTs usually retain expression of SDHB34 and lack mutation in the SDH subunits; rather the mechanism of tumourigenesis in this syndrome seems to be somatic inactivation of the wild-type NF1 allele.35 GIST may also occur in association with other malignancies, either synchronously or metachronously, and may be discovered incidentally during management of other tumours. Second tumours may occur in up to a third of GIST patients; these are commonly gastrointestinal and genitourinary tract carcinomas and haematological malignancies.36,37
MACROSCOPIC FEATURES GIST may range from an innocuous mural or subserosal nodule to a large complex mass which may be transmural in the gastric or intestinal wall, or (less commonly) present as multiple peritoneal nodules. The cut surface ranges from pale and fleshy to haemorrhagic and necrotic, and cystic change is common in larger lesions. Transmural tumours may show a ‘dumbbell’ growth pattern, bulging on either side of the muscularis propria, and tumours which involve the mucosa may develop central ulceration, resulting in an umbilicated appearance, from which catastrophic haemorrhage can occur.
Pathology (2014), 46(2), February
Fig. 1 Typical appearance of spindle cell GIST (H&E).
although a fairly monotonous appearance is common. Mitoses vary from very occasional to abundant, and some more aggressive tumours may have atypical mitoses. Perhaps 25% of gastric tumours have epithelioid morphology, and a number of cases have mixed features. Nuclear pleomorphism is more common in epithelioid tumours, which may have abundant myxoid stroma, particularly in those tumours harbouring a PDGFRA mutation (Fig. 2). Chondroid or osseous metaplasia may also occur (Fig. 3), and occasional tumours show rhabdoid morphology.38 Rarely, some tumours may show abrupt transition from typical KIT-positive spindle cell GIST to a dedifferentiated component which lacks expression of KIT and has a more anaplastic appearance, with high mitotic activity and necrosis. Expression of CD34 is often also lost and de novo expression of other markers including cytokeratin and desmin may develop, leading to diagnostic confusion if the better differentiated component is not sampled. This dedifferentiation can occur de novo or in the setting of imatinib resistance, and does not appear to reflect additional KIT mutations, but may be related to genetic instability with loss of heterozygosity or low level KIT amplification39 (Fig. 4). SDH-deficient GIST is often multiple and typically shows plexiform involvement of muscularis propria, and epithelioid morphology. These tumours are consistently KIT and DOG-1
HISTOLOGY Typical spindle cell GIST (Fig. 1) arising in the stomach or small intestine does not present a particular diagnostic challenge. Most of these tumours are moderately to highly cellular and are relatively monomorphic, with the cells arranged in sheets, ill-defined fascicles or perhaps palisades reminiscent of schwannoma, and in the latter cases paranuclear vacuoles may be prominent. Some tumours are less cellular and display more abundant collagenous stroma, and more aggressive tumours may show some nuclear enlargement and hyperchromasia,
Fig. 2 Gastric GIST with epithelioid morphology and myxoid stroma are likely to harbour PDGFRA mutations (H&E). This case was negative for CD117 but showed diffuse strong positivity for DOG-1.
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THE CHANGING FACE OF GIST: IMPLICATIONS FOR PATHOLOGISTS
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(more likely in the oesophagus) or leiomyosarcoma (for spindle cell GIST), or carcinoma (for epithelioid GIST), or perhaps other mesenchymal tumours such as nerve sheath tumours (particularly if a history of neurofibromatosis is provided) or the rarer mesenchymal malignancies occurring in the gut (such as monophasic synovial sarcoma, gastrointestinal clear cell sarcoma or gastrointestinal Kaposi’s sarcoma). In most cases immunohistochemistry will solve the problem, and in the rare instances where doubt remains, mutational analysis may be helpful.
Fig. 3 Chondroid and/or osseous metaplasia is an infrequent finding in GIST.
positive but negative for SMA. Unusually, these tumours have a propensity to lymph node metastases.25 Immunohistochemically, there is loss of expression of SDHB in all cases, whereas loss of expression of SDHA is only observed in those tumours with SDHA mutations; therefore, the combination of these two markers can be used to direct germline testing (J. Hornick, personal communication). On occasion, GIST may be resected following treatment with tyrosine kinase inhibitors (TKI), administered either as neoadjuvant therapy or in the metastatic setting. Various morphological changes (such as hypocellularity, hyalinised or myxoid stroma, and necrosis, or a change from spindled to epithelioid or pleomorphic cytomorphology) have been described, and KIT expression may be completely lost, as may CD34.40,41 In this context, loss of KIT expression may be a predictor of disease recurrence.42 Complete tumour regression is rarely seen in resected specimens, and apparently viable GIST cells are usually found.43 Rhabdomyosarcomatous differentiation following treatment has also been reported.44 It should be noted that histological response does not appear to correlate well with clinical response.45 Differential diagnosis Depending on the tumour morphology, the most likely differential diagnoses to be entertained would include leiomyoma
Immunohistochemistry Most GISTs (including those which lack KIT mutations) show positivity for CD117 (KIT), which is typically strong and diffuse and may be cytoplasmic or membranous, or show a perinuclear dot pattern. Sometimes KIT staining is weaker or patchy, and it may be negative in those tumours which harbour PDGFRA mutations or are wild-type for both KIT and PDGFRA, or which have been treated with tyrosine kinase inhibitors. Care should be taken to avoid overzealous antigen retrieval, which can produce false-positive staining (a clue to which may be the presence of aberrant staining in adjacent normal tissues such as overlying gastric mucosa). Helpfully, most GISTs (including many paediatric, wild-type, NF1-associated and PDGFRA-mutated tumours) are usually positive for ANO1 (DOG-1).46,47 Staining with this antibody is typically strong and diffuse, and may be cytoplasmic or membranous. Of note, gastrointestinal Kaposi’s sarcoma may express KIT, particularly if antigen retrieval is employed, but DOG-1 is negative.48 Most spindle cell GISTs express CD34, but this is not specific and is of limited diagnostic utility, as are smooth muscle actin, h-caldesmon and desmin. The latter may be helpful in distinguishing between GIST and leiomyoma in that although desmin may be positive in GIST, it is usually weaker and more focal than in true smooth muscle tumours (whereas SMA and h-caldesmon can be diffusely and strongly positive in both). Positivity for keratins (particularly CK18) and S-100 protein may be present but is usually focal or patchy, and relatively weak.
MOLECULAR BIOLOGY KIT The majority (perhaps 85%) of GISTs harbour mutations in the gene encoding the transmembrane tyrosine kinase receptor KIT. These are usually activating mutations leading to ligand-independent dimerisation and constitutive activation of KIT signalling (and thereby activation of downstream effectors, resulting in stimulation of cellular proliferation and/or inhibition of apoptosis). KIT mutations most often arise in the juxtamembrane position at exon 11 (around 67% of GISTs, arising at all anatomical sites), with exons 9 (extracellular domain, 10%, occurring in a higher percentage of intestinal GISTs), 13 (kinase 1 domain, 1%) and 17 (activation loop, 1%) being less commonly affected.32 Most commonly, only one such mutation is found at the time of diagnosis, but second mutations may arise with disease progression; however, a case with two primary mutations at diagnosis has been described.49
Fig. 4 Dedifferentiated GIST: there is abrupt transition from more typical GIST (KIT positive) to an undifferentiated component in which expression of KIT is lost (photograph courtesy of Associate Professor Jason Hornick, Brigham & Women’s Hospital, Boston, USA).
PDGFRA Most GISTs lacking KIT mutations are wild-type (10%) or harbour mutations in platelet-derived growth factor receptor
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(PDGFRA), a tyrosine kinase receptor which is highly homologous with KIT.32 PDGFRA mutations most often occur in exons 12 or 18 and are more common in gastric tumours, which often display a myxoid and epithelioid phenotype. Activation loop mutations at position 842 (D842V) are associated with indolent clinical behaviour but also imatinib resistance, and these patients are generally excluded from adjuvant therapy with TKI.50 KIT and PDGFRA mutations appear to be mutually exclusive. Mutational analysis for KIT and PDGFRA has been shown to have both prognostic and predictive value; for example, patients whose tumours harbour mutations in exon 11 of KIT tend to have superior progression-free survival than those with exon 9 mutations, and the latter may require a higher dose of TKI to achieve a response.51 In Australasia, mutational analysis for KIT and PDGFRA is typically performed prior to commencing TKI therapy, when there is a poor response to such therapy, or when disease progression (such as the development of new metastases) occurs; ‘up-front’ mutational analysis may also be helpful in confirming a diagnosis of GIST when immunohistochemistry is equivocal. Recently it has been reported that free circulating tumour DNA (fcDNA) harbouring KIT or PDGFRA mutations can be detected in plasma in at least some patients.52 Patients with active disease displayed higher amounts of fcDNA than those in remission, and in some patients this declined when the patient responded to treatment, suggesting that this may provide a helpful biomarker for monitoring disease in at least some patients. Other molecular events As described above, mutations in succinate dehydrogenase are associated with a distinctive form of GIST which do not harbour mutations in KIT or PDGFRA and which typically arise in young females. Overexpression of insulin-like growth factor (IGF) has been found in GIST, where it correlated with higher mitotic index, larger size, and a higher risk of relapse and metastasis. IGF-1 and IGF-2 expression both correlated with disease-free survival, which was better if both markers were negative.53 Overexpression of IGF-1R and amplification of the IGF-1R gene have been found to be greater in wild-type and paediatric GIST, compared with those having KIT or PDGFRA mutations,54 and this has subsequently been found to correlate with SDHB-deficient GIST.55,56 Furthermore, inhibition of IGF-1R activity has been shown to result in cytotoxicity and induce apoptosis in GIST cells lines,57 raising the possibility that IGF-1 may drive tumourigenesis in ‘wild-type’ GIST; however, this theory has not gained wide acceptance (J. Hornick, personal communication). A small subset of GIST may harbour V600E mutations in BRAF58 (interestingly, the same point mutation most commonly identified in papillary thyroid carcinoma and subsets of colorectal carcinoma and melanoma). These tumours arose in the small intestine of middle-aged women and were classified as high risk using classical risk stratification indices (discussed further below). This mutation may provide an alternative mechanism of imatinib resistance, and may offer another therapeutic target for a small number of patients.
PROGNOSTICATION Staging For the first time, the 7th Edition of the American Joint Committee on Cancer (AJCC) staging manual and accompanying
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handbook59 included TNM staging parameters for GIST. Like most other predictive models for GIST, this system incorporates mitotic count into the equation, but it is worth noting that lymph node metastases are rare in GIST (except in those harbouring SDH mutations), so that uncharacteristically (when compared with most other tumour types) nodal metastases are grouped with distant metastases as Stage IV, and Stage III is determined on the basis of tumour size and mitotic rate. However, the presence of lymph node metastases should prompt a comment in the pathology report that (particularly in a young female patient), syndromic (SDH-mutant) GIST is a possibility, and in these circumstances immunohistochemistry for SDHB should be performed. Risk stratification Numerous attempts have been made to elaborate reliable predictors of biological behaviour in GIST and stratify patients prognostically, but to date no one such risk stratification schema has proven infallible. The first such guidelines were published following a consensus meeting held in 2001 and proposed categorising GIST as ‘very low’, ‘low’, ‘intermediate’ and ‘high’ risk (of ‘aggressive behaviour’), based on size and mitotic rate (cautioning that ‘. . .it is probably unwise to use the definitive term ‘benign’ for any GIST, at least at the present time’4). These criteria (subsequently known as ‘the NIH system’) were subsequently modified to incorporate anatomical location5 and have formed the basis of what has probably become the most commonly employed risk stratification system currently used worldwide. However, this schema is somewhat flawed and although of some use in stratifying patients statistically, is not entirely reliable in individual cases. Setting aside the significance of syndromic or molecular subtypes (such as those with PDGFRA D842V mutation) in which clinical behaviour may differ, the most obvious difficulty with all of these proposals arises from treating what are essentially continuous variables (such as mitotic rate and size) as discontinuous. Such essentially arbitrary distinctions as ‘more or less than 5 cm’, whilst facilitating statistical analysis, will inevitably introduce ‘grey areas’ on either side of the cut-off points (will a tumour with a diameter of 49 mm really behave markedly less aggressively than one that is 51 mm?). Furthermore, measurements of tumour size and counting of mitoses are subject to intra-observer variability: one observer may press a ruler more firmly onto a soft tumour than would another, squashing it and resulting in a greater diameter being recorded, and one pathologist’s mitosis may be another’s apoptotic figure! In addition, expression of mitotic rates as a number of mitotic figures per 50 high-power fields (HPF) begs the question: ‘how big is a high-power field?’ It is preferable to express the mitotic rate in terms of area, and in the case of GIST, the area described in 50 HPF (as observed by Miettinen and Lasota5) equated to around 5 mm2, which is probably a better way to express the mitotic count. (Notably, in many modern microscopes 5 mm2 is observed in rather less than 50 HPF, perhaps 17–20. Therefore, if the mitotic rate is to be expressed in terms of 50 HPF, at least the field diameter of the reporting pathologist’s microscope should be recorded.) Recognising the arbitrary nature of these binary cut-offs, various authors have developed prognostic nomogram models employing ‘sliding scales’ for one or more of these variables. One such nomogram6 maintains the distinction according to anatomical location (stomach, small intestine, colorectum or ‘other’) and treats size as a continuous variable, but still retains
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THE CHANGING FACE OF GIST: IMPLICATIONS FOR PATHOLOGISTS
Most recently, in a further attempt to improve stratification11 pooled population data from 2560 patients with operable GIST were used to develop prognostic contour maps using non-linear modelling of tumour size and mitotic count, and taking into account tumour site and rupture. This non-linear model was validated in an independent cohort of 920 patients, and was found to predict individual risk of recurrence more accurately than previous models with which this new model was compared (area under the curve 0.88, 95%CI 0.86–0.90) (Fig. 7).
the arbitrary distinction between 65 0.5
0.4
0.3
0.2
0.1
0.01
0.001
Fig. 6 Nomogram for 10-year OS according to patient’s age at diagnosis (65, >65 years). Instructions: The nomogram yields the 10-year OS probability corresponding to a patient’s combination of covariates. Locate the patient’s tumour site and draw a line straight upward to the Points axis to determine the score associated with that site. Repeat the process for tumour size and mitotic index, sum the three resulting scores, and locate the sum on the Total Points axis. Then, on the basis of patient’s age at diagnosis (65 or >65 years), draw a line straight down to the corresponding 10-year OS axis to find OS probability. (Reproduced from Rossi et al.7 with permission from Lippincott Williams and Wilkins.)
1. Clinical information (which should be provided by the referring clinician): tumour location, clinical presentation, known syndromes, prior treatment (neoadjuvant therapy), metastatic or recurrent disease. 2. Macroscopic description: specimen type (including adjacent normal tissues, e.g., wedge resection of gastric wall), tumour size, cut surface, the presence of macroscopic necrosis, haemorrhage and/or tumour rupture, surgical margins. 3. Microscopic findings: tumour morphology (spindled, epithelioid or mixed) and any unusual features, mitoses Table 1
7.
GIST risk stratification schema as proposed by Joensuu60
Risk category
Very low risk Low risk Intermediate risk High risk
4. 5. 6.
Tumour size (cm)
Mitotic index (/50HPF)
Primary tumour site
5.0 2.1–5.0 5.1–10.0
5 5 >5 6–10 5 Any Any >10 >5 >5 5
Any Any Gastric Any Gastric Tumour rupture Any Any Any Non-gastric Non-gastric
8. 9.
(preferably expressed per 5 mm2, or state field diameter of the microscope used), necrosis, lymphovascular invasion, surgical margins, lymph node status (when included). Immunophenotype. Treatment effect (if present). Mutational analysis (where indicated, add a note to this effect). Risk stratification: to some extent which schema is employed will be based on local preference but until such time as one system is clearly shown to be superior, at least one of the recognised systems should be applied. We advocate Joensuu’s modification of the NIH criteria60 (see Table 1) and/or at least one of the nomograms referred to above6,7,11 (see Fig. 5, 6 and 7). AJCC (7th edition) staging parameters.59 Comments: if factors are identified which may indicate a syndrome such as Carney triad, Carney–Stratakis syndrome or familial GIST, these should be commented upon. Epithelioid GIST, especially those occurring in females under the age of 40, should be submitted for SDH immunohistochemistry and if this is negative, it is recommended that a comment be made to the effect that Carney–Stratakis syndrome or Carney triad should be considered and appropriate clinical surveillance be instituted.27
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THE CHANGING FACE OF GIST: IMPLICATIONS FOR PATHOLOGISTS
Gastric, rupture unknown
Non-gastric, rupture unknown
147
E-GIST, rupture unknown
Mitotic count
50
A
25 15 10 5 2
Mitotic count
50
D
B
0 Gastric with no rupture
C Non-gastric with no rupture
E-GIST with no rupture
25 15 10 5 2
E
0
F Non-gastric with rupture
Gastric with rupture
E-GIST with rupture
Mitotic count
50
G
25 15 10 5 2 0 0.1
2
0% 10% 20%
5 10 15 Tumour size (cm) 40%
60%
25
H
0.1
2
5 10 15 Tumour size (cm)
25
I
0.1
2
5 10 15 Tumour size (cm)
25
80% 90% 100%
Fig. 7 Contour maps for estimating the risk of GIST recurrence after surgery. The upper row maps are used when tumour rupture status is unknown (A–C), the middle row maps when the tumour has not ruptured (D–F), and the bottom row maps when tumour rupture has occurred (G–I). Red areas depict high risk, blue areas low risk, and white areas indicate lack of data. The percentages associated with each colour (key) indicate the probability of GIST recurrence within the first 10 years of follow-up after surgery. For example, the middle map of the far left column (D) shows that the 10-year risk of GIST recurrence of a patient diagnosed with a 10 cm gastric GIST with 5 mitoses per 50 high power fields (HPFs) of the microscope and no rupture is 20–40%. The 10-year risk associated with a similar tumour when the mitosis count is 10 per 50 HPFs increases to 40–60%. E-GIST, extragastrointestinal stromal tumour (arising outside the gastrointestinal tract). (Reproduced from Joensuu et al.11 with permission from Elsevier.)
Conflicts of interest and sources of funding: The authors state that there are no conflicts of interest to disclose. Address for correspondence: Dr C. Hemmings, SJOG Pathology, Level 5, Bendat Family Comprehensive Cancer Centre, 12 Salvado Rd, Subiaco, WA 6008, Australia. E-mail: [email protected]
8.
9.
References 1. Miettinen M, Corless C, Lasota J, et al. Gastrointestinal stromal tumours. In: Fletcher C, Bridge J, Hogendoorn C, Mertens F, editors. WHO Classification of Tumours of Soft Tissue and Bone. 4th ed. Lyon: IARC Press, 2013. 2. Agaimy A, Wunsch P, Hofstaedter F, et al. Minute gastric sclerosing stromal tumors (GIST tumorlets) are common in adults and frequently show c-KIT mutations. Am J Surg Pathol 2007; 31: 113–20. 3. Kawanowa K, Sakuma Y, Sakurai S, et al. High incidence of microscopic gastrointestinal stromal tumors in the stomach. Hum Pathol 2006; 37: 1527–35. 4. Fletcher C, Berman J, Corless C, et al. Diagnosis of gastrointestinal stromal tumors: A consensus approach. Hum Pathol 2002; 33: 459–65. 5. Miettinen M, Lasota J. Gastrointestinal stromal tumors: pathology and prognosis at different sites. Semin Diagn Pathol 2006; 23: 70–83. 6. Gold J, Gonen M, Gutierrez A, et al. Development and validation of a prognostic nomogram for recurrence-free survival after complete surgical resection of localised primary gastrointestinal stromal tumour: a retrospective analysis. Lancet Oncol 2009; 10: 1045–52. 7. Rossi S, Miceli R, Messerini L, et al. Natural history of imatinib-naive GISTs: a retrospective analysis of 929 cases with long-term follow-up and
10. 11. 12. 13.
14. 15. 16.
development of a survival nomogram based on mitotic index and size as continuous variables. Am J Surg Pathol 2011; 35: 1646–56. Stratakis C, Carney J. The triad of paragangliomas, gastric stromal tumours and pulmonary chondromas (Carney triad), and the dyad of paragangliomas and gastric stromal sarcomas (Carney-Stratakis syndrome): molecular genetics and clinical implications. J Intern Med 2009; 266: 43–52. Pasini B, McWhinney S, Bei T, 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; 16: 79–88. Lv A, Li Z, Tian X, et al. SKP2 high expression, KIT exon 11 deletions,;1; and gastrointestinal bleeding as predictors of poor prognosis in primary gastrointestinal stromal tumors. PLoS ONE 2013; 8: e62951. Joensuu H, Vehtari J, Nishida T, et al. Risk of recurrence of gastrointestinal stromal tumour after surgery: an analysis of pooled population-based cohorts. Lancet Oncol 2012; 13: 265–74. Miettinen M, Sobin L, Lasota J. Gastrointestinal stromal tumors presenting as omental masses – A clinicopathologic analysis of 95 cases. Am J Surg Pathol 2009; 33: 1267–75. Long K, Butrynski J, Blank S, et al. Primary extragastrointestinal stromal tumor of the pleura: report of a unique case with genetic confirmation. Am J Surg Pathol 2010; 34: 907–12. Irving J, Lerwill M, Young R. Gastrointestinal stromal tumors metastatic to the ovary: A report of five cases. Am J Surg Pathol 2005; 29: 920–6. Hughes B, Yip D, Goldstein D, et al. Cerebral relapse of metastatic gastrointestinal stromal tumor during treatment with imatinib mesylate: case report. BMC Cancer 2004; 4: 74. Jati A, Tatli S, Morgan J, et al. Imaging features of bone metastases in patients with gastrointestinal stromal tumors. Diagn Interv Radiol 2012; 18: 391–6.
Copyright © Royal College of pathologists of Australasia. Unauthorized reproduction of this article is prohibited.
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17. Nilsson B, Bumming P, Meis-Kindblom J, et al. Gastrointestinal stromal tumors: the incidence, the prevalence, clinical course and prognostication in the preimatinib mesylate era: A population-based study in western Sweden. Cancer 2005; 103: 821–9. 18. Carney J, Sheps S, Go V, Gordon H. The triad of gastric leiomyosarcoma, functioning extra-adrenal paraganglioma and pulmonary chondroma. N Engl J Med 1977; 296: 1517–8. 19. Carney J, Stratakis C. Familial paraganglioma and gastric stromal sarcoma: a new syndrome distinct from Carney triad. Am J Med Genet 2002; 108: 132–9. 20. McWhinney S, Pasini B, Stratakis C. Familial gastrointestinal stromal tumors and germ-line mutations. N Engl J Med 2007; 357: 1054–6. 21. Miettinen M, Killian J, Wang Z, et al. Immunohistochemical loss of succinate dehydrogenase subunit A (SDHA) in gastrointestinal stromal tumors (GISTs) signals SDHA germline mutation. Am J Surg Pathol 2013; 37: 234–40. 22. Dwight T, Benn D, Clarkson A, et al. Loss of SDHA expression identifies SHDA mutations in succinate dehydrogenase-deficient gastrointestinal stromal tumors. Am J Surg Pathol 2013; 37: 226–33. 23. Postow M, Robson M. Inherited gastrointestinal stromal tumor syndromes: mutations, clinical features, and therapeutic implications. Clin Sarcoma Res 2012; 2: 16. 24. Matyakhina L, Bei T, McWhinney S, et al. Genetics of Carney triad: Recurrent losses at chromosome 1 but lack of germline mutations in genes associated with paragangliomas and gastrointestinal stromal tumors. J Clin Endocrinol Metab 2007; 92: 2938–43. 25. Miettinen M, Wang Z, Sarlomo-Rikala M, et al. Succinate dehydrogenasedeficient GISTs: A clinicopathologic, immunohistochemical, and molecular genetic study of 66 gastric GISTs with predilection to young age. Am J Surg Pathol 2011; 35: 1712–21. 26. Wagner A, Remillard S, Zhang Y, et al. Loss of expression of SDHA predicts SHDA mutations in gastrointestinal stromal tumors. Mod Pathol 2013; 26: 289–94. 27. Gaal J, Stratakis C, Carney J, et al. SDHB immunohistochemistry: A useful took in the diagnosis of Carney-Stratakis and Carney triad gastrointestinal stromal tumors. Mod Pathol 2011; 24: 147–51. 28. Chompret A, Kannengiesser C, Barrois M, et al. PDGFRA germline mutation in a family with multiple cases of gastrointestinal stromal tumor. Gastroenterology 2004; 126: 318–21. 29. Neuhann T, Mansmann V, Merkelbach-Bruse S, et al. A novel germline mutation (p.L576P) in a family presenting with juvenile onset of multiple gastrointestinal stromal tumors, skin hyperpigmentations, and esophageal stenosis. Am J Surg Pathol 2013; 37: 898–905. 30. Carballo M, Roig I, Aguilar F, et al. Novel c-KIT germline mutation in a family with gastrointestinal stromal tumors and cutaneous hyperpigmentation. Am J Med Genet A 2005; 132: 361–4. 31. Maeyama H, Hidaka E, Ota H, et al. Familial gastrointestinal stromal tumor with hyperpigmentation: association with a germline mutation of the c-kit gene. Gastroenterology 2001; 120: 210–5. 32. Miettinen M, Lasota J. Gastrointestinal stromal tumors: Review on morphology, molecular pathology, prognosis and differential diagnosis. Arch Pathol Lab Med 2006; 130: 1466–78. 33. Mussi C, Schildhaus H, Gronchi A, et al. Therapeutic consequences from molecular biology for gastrointestinal stromal tumor patients affected by neurofibromatosis type I. Clin Cancer Res 2008; 14: 4550–5. 34. Wang J, Lasota J, Miettinen M. Succinate dehydrogenase subunit B (SDHB) is expressed in neurofibromatosis 1-associated gastrointestinal stromal tumors (GISTs): Implications for the SDHB expression based classification of GISTs. J Cancer 2011; 16: 90–3. 35. Maertens O, Prenen H, Debiec-Rychter M, et al. Molecular pathogenesis of multiple gastrointestinal stromal tumors in NF1 patients. Hum Mol Genet 2006; 15: 1015–23. 36. Ponti G, Luppi G, Martorana D, et al. Gastrointestinal stromal tumor and other primary metachronous or synchronous neoplasms as a suspicion criterion for syndromic setting. Oncol Reports 2012; 23: 437–44. 37. Miettinen M, Kraszewska E, Sobin L, Lasota J. A nonrandom association between gastrointestinal stromal tumors and myeloid leukaemia. Cancer 2008; 112: 645–9. 38. Hanson J, Trent J, Yang D, Cooper K. Small-intestinal rhabdoid gastrointestinal stromal tumor (GIST): Mutation analysis and clinical implications of a rare morphological variant. Int J Surg Pathol 2011; 19: 653–7. 39. Antonescu C, Romeo S, Zhang L, et al. Dedifferentiation in gastrointestinal stromal tumor to an anaplastic KIT-negative phenotype: a diagnostic pitfall: morphologic and molecular characterization of 8 cases occurring either de novo or after imatinib therapy. Am J Surg Pathol 2013; 37: 385–92. 40. Pauwels P, Debiec-Rychter M, Stul M, et al. Changing phenotype of gastrointestinal stromal tumours under imatinib mesylate treatment: A potential diagnostic pitfall. Histopathology 2005; 47: 41–7. 41. Koh Y, Lee H, Ohn D, et al. The lack of CD34 expression in gastrointestinal stromal tumors is related to cystic degeneration following imatinib use. Jpn J Clin Oncol 2012; 42: 1020–7.
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42. Mearadji A, den Bakker M, van Geel A, et al. Decrease of CD117 expression as possible prognostic marker for recurrence in the resected specimen after imatinib treatment in patients with initially unresectable gastrointestinal stromal tumors: A clinicopathological analysis. Anticancer Drugs 2008; 19: 607–12. 43. Rutkowski P, Nowecki Z, Nyckowski P, et al. Surgical treatment of patients with initially inoperable and/or metastatic gastrointestinal stromal tumors (GIST) during therapy with imatinib mesylate. J Surg Oncol 2006; 93: 304–11. 44. Liegl B, Hornick J, Antonescu C, et al. Rhabdomyosarcomatous differentiation in gastrointestinal stromal tumors after tyrosine kinase inhibitor therapy: A novel form of tumor progression. Am J Surg Pathol 2009; 33: 218–26. 45. Agaram N, Besmer P, Wong G, et al. Pathologic and molecular heterogeneity in imatinib-stable or imatinib-responsive gastrointestinal stromal tumors. Clin Cancer Res 2007; 13: 170–81. 46. West R, Corless C, Chen X, et al. The novel marker, DOG1, is expressed ubiquitously in gastrointestinal stromal tumors irrespective of KIT or PDGFRA mutation status. Am J Pathol 2004; 165: 107–13. 47. Liegl B, Hornick J, Corless C, Fletcher C. Monoclonal antibody DOG1.1 shows higher sensitivity than KIT in the diagnosis of gastrointestinal stromal tumors, including unusual subtypes. Am J Surg Pathol 2009; 33: 437–46. 48. Parfitt J, Rodriguez-Justo M, Feakings R, Novelli M. Gastrointestinal Kaposi’s sarcoma: CD117 expression and the potential for misdiagnosis as gastrointestinal stromal tumour. Histopathology 2008; 52: 816–23. 49. Malik L, Hemmings C, Beshay V, et al. Metastatic gastrointestinal stromal tumour of the ileum with dual primary c-KIT missence (sic) mutations. Pathology 2013; 45: 604–6. 50. Casali P, Fumagalli E, Gronchi A. Adjuvant therapy of gastrointestinal stormal tumors (GIST). Curr Treat Options Oncol 2013; 13: 277–84. 51. Gastrointestinal Stromal Tumor Meta-Analysis Group (MetaGIST)Comparison of two doses of imatinib for the treatment of unresectable or metastatic gastrointestinal stromal tumors: A meta-analysis of 1,640 patients. J Clin Oncol 2010; 28: 1247–53. 52. Maier J, Lange T, Kerle I, et al. Detection of mutant free circulating tumor DNA in the plasma of patients with gastrointestinal stromal tumor harbouring activating mutations of CKIT or PDGFRA. Clin Cancer Res 2013; 19: 4854–67. 53. Braconi C, Bracci R, Bearzi I, et al. Insulin-like growth factor (IGF) 1 and 2 help to predict disease outcome in GIST patients. Ann Oncol 2008; 19: 1293–8. 54. Rink L, Godwin A. Clinical and molecular characteristics of gastrointestinal stromal tumor in the pediatric and young adult population. Curr Oncol Rep 2009; 11: 314–21. 55. Chou A, Chen J, Clarkson A, et al. Succinate dehydrogenase-deficient GISTs are characterized by IGF1R overexpression. Mod Pathol 2012; 25: 1307–13. 56. Lasota J, Wang Z, Kim S, et al. Expression of the receptor for type I insulinlike growth factor (IGF1R) in gastrointestinal stromal tumors: An immunohistochemical study of 1078 cases with diagnostic and therapeutic implications. Am J Surg Pathol 2013; 37: 114–9. 57. Tarn C, Rink L, Merkel E, et al. Insulin-like growth factor 1 receptor is a potential therapeutic target for gastrointestinal stromal tumors. Proc Natl Acad Sci USA 2008; 105: 8387–92. 58. Agaram N, Wong G, Guo T, et al. Novel V600E BRAF mutations in imatinib-naı¨ve and imatinib-resistant gastrointestinal stromal tumours. Genes Chromosomes Cancer 2008; 47: 853–9. 59. Edge S, Byrd D, Compton C, et al. Cancer Staging Handbook. 7th ed. New York: Springer, 2010. Chapter 16, Gastrointestinal stromal tumor. 60. Joensuu H. Risk stratification of patients diagnosed with gastrointestinal stromal tumor. Hum Pathol 2008; 39: 1411–9. 61. Takahashi T, Nakajima K, Nishitani A, et al. An enhanced risk-group stratification system for more practical prognostication of clinically malignant gastrointestinal stromal tumors. Int J Clin Oncol 2007; 12: 369–74. 62. Rutkowski P, Bylina E, Wozniak A, et al. Validation of the Joensuu risk criteria for primary resectable gastrointestinal stromal tumour – The impact of tumour rupture on patient outcomes. Eur J Surg Oncol 2011; 37: 890–6. 63. Sabah M, Cummins R, Leader M, Kay E. Altered expression of cell cycle regulatory proteins in gastrointestinal stromal tumors: Markers with potential prognostic implications. Hum Pathol 2006; 37: 648–55. 64. Steinert D, Oyarzo M, Wang X, et al. Expresion of Bcl-2 in gastrointestinal stromal tumors: correlation with progression-free survival in 81 patients treated with imatinib mesylate. Cancer 2006; 106: 1617–23. 65. Montgomery E, Abraham S, Fisher C, et al. CD44 loss in gastric stromal tumors as a prognostic marker. Am J Surg Pathol 2004; 28: 168–77. 66. Wong N, Young R, Malcomson R, et al. Prognostic indicators for gastrointestinal stromal tumours: A clinicopathological and immunohistochemical study of 108 resected cases of the stomach. Histopathol 2003; 43: 118– 26.
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SOFT TISSUE PATHOLOGY
The changing face of GIST: implications for pathologists CHRIS HEMMINGS1,2
AND
DESMOND YIP3,4
1St John of God Pathology Subiaco, 2School of Surgery, University of Western Australia, Western Australia, 3Department of Medical Oncology, The Canberra Hospital, and 4ANU Medical School, Australian National
University, Canberra, Australian Capital Territory, Australia
Summary Gastrointestinal stromal tumour (GIST) is now recognised as the most common primary mesenchymal tumour of the gut. A number of different parameters have been identified to aid prediction of clinical behaviour, but prognostication for an individual remains difficult. The pathologist plays a crucial role in guiding management of these tumours, but is faced with a number of challenges in so doing. This review describes the variable pathological features that may be encountered, and examines some of the issues in the pathology reporting of GIST and attempts to provide some guidance in factors that should be addressed in a comprehensive pathology report. Key words: Gastrointestinal stromal tumour, histopathology, immunohistochemistry, KIT, mutational analysis, PDGFRA, risk stratification, SDHB, SDHB. Received 5 September, revised and accepted 15 September 2013
INTRODUCTION Gastrointestinal stromal tumour (GIST) is now recognised as the most common primary mesenchymal tumour of the gut, having an annual incidence of around 11–15 per 100,000 (based on Scandinavian population-based studies).1 If incidental microscopic GISTs (for example, found at surgery for gastric or oesophageal cancer or at autopsy) are included, the frequency is much greater; perhaps 1 in 10 or more. (It has been suggested that up to 20% of the population may harbour micro-GIST, although only a small fraction of these will develop clinically significant tumours.2,3) Since GIST became recognised towards the end of last century, there has been an expansion in our understanding of not only the biology of this fascinating tumour, but of the spectrum of histological appearances and clinical features that it may show. Histologically similar tumours span a clinical spectrum from benign to aggressively malignant, and this has lead to a number of attempts4–11 to better identify pathological features (both morphological and molecular) that may predict subsequent behaviour, or suggest a specific clinical syndrome. Nonetheless, predicting how a particular patient’s tumour will behave remains imperfect, and the pathologist is faced with a bewildering array of options when formulating a report. This review examines some of the issues in the pathology reporting of GIST and attempts to provide some guidance as to factors that should be addressed.
CLINICAL FEATURES More than half of all GIST occur in the stomach and about another third in the small intestine (particularly the jejunum and Print ISSN 0031-3025/Online ISSN 1465-3931 DOI: 10.1097/PAT.0000000000000047
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ileum), around 5% in the colorectum and only about 1% in the oesophagus, where leiomyoma is the most common mesenchymal tumour. Despite initial debate about their true origin (metastasis from an occult intestinal primary or ‘decapitated’ extension from a mural tumour versus truly extraintestinal origin),12 uncommon cases of extraintestinal GIST (arising within mesentery or omentum) are now generally accepted to occur, and at least one credible example of primary GIST arising outside the abdomen has been reported.13 Non-syndromic GIST typically occurs in older adults (median age around 60 years),1 with perhaps a slight male preponderance, whereas syndromic GIST tends to occur at a younger age and, in the case of SDH-deficient GIST, more commonly in females. The most common clinical presentations include gastrointestinal bleeding, vague abdominal complaints and incidental findings. Gastric outlet obstruction is rare1 but small intestinal tumours may cause obstruction with or without intussusception. Malignant GISTs typically disseminate by coelomic spread within the abdomen and/or metastasis to the liver, and less frequently to other organs such as ovary.14 Extra-abdominal metastasis is extremely unusual, but has been reported.15–17 Syndromes and associations Most GISTs arise sporadically, but they may also occur in association with a number of clinical syndromes, which may only be recognised when the patient presents with GIST. These include Carney triad (GIST, pulmonary chondroma and paraganglioma), Carney–Stratakis syndrome (GIST and paraganglioma), familial GIST syndrome and neurofibromatosis type 1 (NF1). Carney triad was first described in 197718 and is thought to be non-hereditary. GISTs occurring in Carney triad tend to arise in the gastric antrum of females and display epithelioid morphology, and typically present at a younger age than sporadic GISTs (including in children). The existence of a syndrome of familial paraganglioma and GIST, different from the previously described Carney triad, was proposed in 200219 and has subsequently become known as Carney–Stratakis syndrome. This syndrome is inherited in an autosomal dominant fashion but with incomplete penetrance, and displays a variable clinical phenotype. The underlying molecular pathogenesis was subsequently found to be any of several germline mutations in the genes encoding one or other subunit of succinate dehydrogenase (SDH),20–22 an enzyme involved in cellular respiration but also thought to function as a tumour suppressor.23 (By comparison, subsequent analysis of tumours associated with Carney triad found no coding sequence mutations in SDH genes, although copy number changes were
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seen.24) Functional loss of the SDH complex can be identified immunohistochemically by loss of expression of SDH subunits,21,25–27 and this will be observed in a significant proportion of all gastric GISTs occurring under the age of 40, including nearly all of those under 20 years. There is a preponderance of female patients of over 2:1 in this group.25 Overall, perhaps 5% of all GISTs are SDH-deficient, although only around half of these harbour SDH mutations; this includes a small subset of apparently sporadic GISTs arising in adults, as well as the vast majority of GISTs arising in children, and those associated with either Carney–Stratakis syndrome or Carney triad (J. Hornick, personal communication). The rare familial GIST syndrome is associated with various germline mutations in KIT or PDGFRA, usually inherited in an autosomal dominant manner. These patients tend to develop multiple lesions throughout the gastrointestinal tract, often from a young age, and typically display cutaneous hyperpigmentation, which may predate the development of GIST.23,28–31 Patients with NF1 are at increased risk of developing GIST, which most commonly arise in the small intestine and are often multifocal and associated with diffuse ICC (Interstitial Cell of Cajal) hyperplasia.32 These tumours usually have spindle cell morphology with infrequent mitoses and may lack KIT (CD117) positivity,5 but CD34 and DOG-1 are usually expressed. Despite the finding that haemorrhage and necrosis (normally worrisome features) are relatively common, clinical behaviour tends to be indolent, but when treated, primary imatinib resistance is common.33 Although typically wild-type for both KIT and PDGFRA mutations, NF1-associated GISTs usually retain expression of SDHB34 and lack mutation in the SDH subunits; rather the mechanism of tumourigenesis in this syndrome seems to be somatic inactivation of the wild-type NF1 allele.35 GIST may also occur in association with other malignancies, either synchronously or metachronously, and may be discovered incidentally during management of other tumours. Second tumours may occur in up to a third of GIST patients; these are commonly gastrointestinal and genitourinary tract carcinomas and haematological malignancies.36,37
MACROSCOPIC FEATURES GIST may range from an innocuous mural or subserosal nodule to a large complex mass which may be transmural in the gastric or intestinal wall, or (less commonly) present as multiple peritoneal nodules. The cut surface ranges from pale and fleshy to haemorrhagic and necrotic, and cystic change is common in larger lesions. Transmural tumours may show a ‘dumbbell’ growth pattern, bulging on either side of the muscularis propria, and tumours which involve the mucosa may develop central ulceration, resulting in an umbilicated appearance, from which catastrophic haemorrhage can occur.
Pathology (2014), 46(2), February
Fig. 1 Typical appearance of spindle cell GIST (H&E).
although a fairly monotonous appearance is common. Mitoses vary from very occasional to abundant, and some more aggressive tumours may have atypical mitoses. Perhaps 25% of gastric tumours have epithelioid morphology, and a number of cases have mixed features. Nuclear pleomorphism is more common in epithelioid tumours, which may have abundant myxoid stroma, particularly in those tumours harbouring a PDGFRA mutation (Fig. 2). Chondroid or osseous metaplasia may also occur (Fig. 3), and occasional tumours show rhabdoid morphology.38 Rarely, some tumours may show abrupt transition from typical KIT-positive spindle cell GIST to a dedifferentiated component which lacks expression of KIT and has a more anaplastic appearance, with high mitotic activity and necrosis. Expression of CD34 is often also lost and de novo expression of other markers including cytokeratin and desmin may develop, leading to diagnostic confusion if the better differentiated component is not sampled. This dedifferentiation can occur de novo or in the setting of imatinib resistance, and does not appear to reflect additional KIT mutations, but may be related to genetic instability with loss of heterozygosity or low level KIT amplification39 (Fig. 4). SDH-deficient GIST is often multiple and typically shows plexiform involvement of muscularis propria, and epithelioid morphology. These tumours are consistently KIT and DOG-1
HISTOLOGY Typical spindle cell GIST (Fig. 1) arising in the stomach or small intestine does not present a particular diagnostic challenge. Most of these tumours are moderately to highly cellular and are relatively monomorphic, with the cells arranged in sheets, ill-defined fascicles or perhaps palisades reminiscent of schwannoma, and in the latter cases paranuclear vacuoles may be prominent. Some tumours are less cellular and display more abundant collagenous stroma, and more aggressive tumours may show some nuclear enlargement and hyperchromasia,
Fig. 2 Gastric GIST with epithelioid morphology and myxoid stroma are likely to harbour PDGFRA mutations (H&E). This case was negative for CD117 but showed diffuse strong positivity for DOG-1.
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THE CHANGING FACE OF GIST: IMPLICATIONS FOR PATHOLOGISTS
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(more likely in the oesophagus) or leiomyosarcoma (for spindle cell GIST), or carcinoma (for epithelioid GIST), or perhaps other mesenchymal tumours such as nerve sheath tumours (particularly if a history of neurofibromatosis is provided) or the rarer mesenchymal malignancies occurring in the gut (such as monophasic synovial sarcoma, gastrointestinal clear cell sarcoma or gastrointestinal Kaposi’s sarcoma). In most cases immunohistochemistry will solve the problem, and in the rare instances where doubt remains, mutational analysis may be helpful.
Fig. 3 Chondroid and/or osseous metaplasia is an infrequent finding in GIST.
positive but negative for SMA. Unusually, these tumours have a propensity to lymph node metastases.25 Immunohistochemically, there is loss of expression of SDHB in all cases, whereas loss of expression of SDHA is only observed in those tumours with SDHA mutations; therefore, the combination of these two markers can be used to direct germline testing (J. Hornick, personal communication). On occasion, GIST may be resected following treatment with tyrosine kinase inhibitors (TKI), administered either as neoadjuvant therapy or in the metastatic setting. Various morphological changes (such as hypocellularity, hyalinised or myxoid stroma, and necrosis, or a change from spindled to epithelioid or pleomorphic cytomorphology) have been described, and KIT expression may be completely lost, as may CD34.40,41 In this context, loss of KIT expression may be a predictor of disease recurrence.42 Complete tumour regression is rarely seen in resected specimens, and apparently viable GIST cells are usually found.43 Rhabdomyosarcomatous differentiation following treatment has also been reported.44 It should be noted that histological response does not appear to correlate well with clinical response.45 Differential diagnosis Depending on the tumour morphology, the most likely differential diagnoses to be entertained would include leiomyoma
Immunohistochemistry Most GISTs (including those which lack KIT mutations) show positivity for CD117 (KIT), which is typically strong and diffuse and may be cytoplasmic or membranous, or show a perinuclear dot pattern. Sometimes KIT staining is weaker or patchy, and it may be negative in those tumours which harbour PDGFRA mutations or are wild-type for both KIT and PDGFRA, or which have been treated with tyrosine kinase inhibitors. Care should be taken to avoid overzealous antigen retrieval, which can produce false-positive staining (a clue to which may be the presence of aberrant staining in adjacent normal tissues such as overlying gastric mucosa). Helpfully, most GISTs (including many paediatric, wild-type, NF1-associated and PDGFRA-mutated tumours) are usually positive for ANO1 (DOG-1).46,47 Staining with this antibody is typically strong and diffuse, and may be cytoplasmic or membranous. Of note, gastrointestinal Kaposi’s sarcoma may express KIT, particularly if antigen retrieval is employed, but DOG-1 is negative.48 Most spindle cell GISTs express CD34, but this is not specific and is of limited diagnostic utility, as are smooth muscle actin, h-caldesmon and desmin. The latter may be helpful in distinguishing between GIST and leiomyoma in that although desmin may be positive in GIST, it is usually weaker and more focal than in true smooth muscle tumours (whereas SMA and h-caldesmon can be diffusely and strongly positive in both). Positivity for keratins (particularly CK18) and S-100 protein may be present but is usually focal or patchy, and relatively weak.
MOLECULAR BIOLOGY KIT The majority (perhaps 85%) of GISTs harbour mutations in the gene encoding the transmembrane tyrosine kinase receptor KIT. These are usually activating mutations leading to ligand-independent dimerisation and constitutive activation of KIT signalling (and thereby activation of downstream effectors, resulting in stimulation of cellular proliferation and/or inhibition of apoptosis). KIT mutations most often arise in the juxtamembrane position at exon 11 (around 67% of GISTs, arising at all anatomical sites), with exons 9 (extracellular domain, 10%, occurring in a higher percentage of intestinal GISTs), 13 (kinase 1 domain, 1%) and 17 (activation loop, 1%) being less commonly affected.32 Most commonly, only one such mutation is found at the time of diagnosis, but second mutations may arise with disease progression; however, a case with two primary mutations at diagnosis has been described.49
Fig. 4 Dedifferentiated GIST: there is abrupt transition from more typical GIST (KIT positive) to an undifferentiated component in which expression of KIT is lost (photograph courtesy of Associate Professor Jason Hornick, Brigham & Women’s Hospital, Boston, USA).
PDGFRA Most GISTs lacking KIT mutations are wild-type (10%) or harbour mutations in platelet-derived growth factor receptor
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(PDGFRA), a tyrosine kinase receptor which is highly homologous with KIT.32 PDGFRA mutations most often occur in exons 12 or 18 and are more common in gastric tumours, which often display a myxoid and epithelioid phenotype. Activation loop mutations at position 842 (D842V) are associated with indolent clinical behaviour but also imatinib resistance, and these patients are generally excluded from adjuvant therapy with TKI.50 KIT and PDGFRA mutations appear to be mutually exclusive. Mutational analysis for KIT and PDGFRA has been shown to have both prognostic and predictive value; for example, patients whose tumours harbour mutations in exon 11 of KIT tend to have superior progression-free survival than those with exon 9 mutations, and the latter may require a higher dose of TKI to achieve a response.51 In Australasia, mutational analysis for KIT and PDGFRA is typically performed prior to commencing TKI therapy, when there is a poor response to such therapy, or when disease progression (such as the development of new metastases) occurs; ‘up-front’ mutational analysis may also be helpful in confirming a diagnosis of GIST when immunohistochemistry is equivocal. Recently it has been reported that free circulating tumour DNA (fcDNA) harbouring KIT or PDGFRA mutations can be detected in plasma in at least some patients.52 Patients with active disease displayed higher amounts of fcDNA than those in remission, and in some patients this declined when the patient responded to treatment, suggesting that this may provide a helpful biomarker for monitoring disease in at least some patients. Other molecular events As described above, mutations in succinate dehydrogenase are associated with a distinctive form of GIST which do not harbour mutations in KIT or PDGFRA and which typically arise in young females. Overexpression of insulin-like growth factor (IGF) has been found in GIST, where it correlated with higher mitotic index, larger size, and a higher risk of relapse and metastasis. IGF-1 and IGF-2 expression both correlated with disease-free survival, which was better if both markers were negative.53 Overexpression of IGF-1R and amplification of the IGF-1R gene have been found to be greater in wild-type and paediatric GIST, compared with those having KIT or PDGFRA mutations,54 and this has subsequently been found to correlate with SDHB-deficient GIST.55,56 Furthermore, inhibition of IGF-1R activity has been shown to result in cytotoxicity and induce apoptosis in GIST cells lines,57 raising the possibility that IGF-1 may drive tumourigenesis in ‘wild-type’ GIST; however, this theory has not gained wide acceptance (J. Hornick, personal communication). A small subset of GIST may harbour V600E mutations in BRAF58 (interestingly, the same point mutation most commonly identified in papillary thyroid carcinoma and subsets of colorectal carcinoma and melanoma). These tumours arose in the small intestine of middle-aged women and were classified as high risk using classical risk stratification indices (discussed further below). This mutation may provide an alternative mechanism of imatinib resistance, and may offer another therapeutic target for a small number of patients.
PROGNOSTICATION Staging For the first time, the 7th Edition of the American Joint Committee on Cancer (AJCC) staging manual and accompanying
Pathology (2014), 46(2), February
handbook59 included TNM staging parameters for GIST. Like most other predictive models for GIST, this system incorporates mitotic count into the equation, but it is worth noting that lymph node metastases are rare in GIST (except in those harbouring SDH mutations), so that uncharacteristically (when compared with most other tumour types) nodal metastases are grouped with distant metastases as Stage IV, and Stage III is determined on the basis of tumour size and mitotic rate. However, the presence of lymph node metastases should prompt a comment in the pathology report that (particularly in a young female patient), syndromic (SDH-mutant) GIST is a possibility, and in these circumstances immunohistochemistry for SDHB should be performed. Risk stratification Numerous attempts have been made to elaborate reliable predictors of biological behaviour in GIST and stratify patients prognostically, but to date no one such risk stratification schema has proven infallible. The first such guidelines were published following a consensus meeting held in 2001 and proposed categorising GIST as ‘very low’, ‘low’, ‘intermediate’ and ‘high’ risk (of ‘aggressive behaviour’), based on size and mitotic rate (cautioning that ‘. . .it is probably unwise to use the definitive term ‘benign’ for any GIST, at least at the present time’4). These criteria (subsequently known as ‘the NIH system’) were subsequently modified to incorporate anatomical location5 and have formed the basis of what has probably become the most commonly employed risk stratification system currently used worldwide. However, this schema is somewhat flawed and although of some use in stratifying patients statistically, is not entirely reliable in individual cases. Setting aside the significance of syndromic or molecular subtypes (such as those with PDGFRA D842V mutation) in which clinical behaviour may differ, the most obvious difficulty with all of these proposals arises from treating what are essentially continuous variables (such as mitotic rate and size) as discontinuous. Such essentially arbitrary distinctions as ‘more or less than 5 cm’, whilst facilitating statistical analysis, will inevitably introduce ‘grey areas’ on either side of the cut-off points (will a tumour with a diameter of 49 mm really behave markedly less aggressively than one that is 51 mm?). Furthermore, measurements of tumour size and counting of mitoses are subject to intra-observer variability: one observer may press a ruler more firmly onto a soft tumour than would another, squashing it and resulting in a greater diameter being recorded, and one pathologist’s mitosis may be another’s apoptotic figure! In addition, expression of mitotic rates as a number of mitotic figures per 50 high-power fields (HPF) begs the question: ‘how big is a high-power field?’ It is preferable to express the mitotic rate in terms of area, and in the case of GIST, the area described in 50 HPF (as observed by Miettinen and Lasota5) equated to around 5 mm2, which is probably a better way to express the mitotic count. (Notably, in many modern microscopes 5 mm2 is observed in rather less than 50 HPF, perhaps 17–20. Therefore, if the mitotic rate is to be expressed in terms of 50 HPF, at least the field diameter of the reporting pathologist’s microscope should be recorded.) Recognising the arbitrary nature of these binary cut-offs, various authors have developed prognostic nomogram models employing ‘sliding scales’ for one or more of these variables. One such nomogram6 maintains the distinction according to anatomical location (stomach, small intestine, colorectum or ‘other’) and treats size as a continuous variable, but still retains
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THE CHANGING FACE OF GIST: IMPLICATIONS FOR PATHOLOGISTS
Most recently, in a further attempt to improve stratification11 pooled population data from 2560 patients with operable GIST were used to develop prognostic contour maps using non-linear modelling of tumour size and mitotic count, and taking into account tumour site and rupture. This non-linear model was validated in an independent cohort of 920 patients, and was found to predict individual risk of recurrence more accurately than previous models with which this new model was compared (area under the curve 0.88, 95%CI 0.86–0.90) (Fig. 7).
the arbitrary distinction between 65 0.5
0.4
0.3
0.2
0.1
0.01
0.001
Fig. 6 Nomogram for 10-year OS according to patient’s age at diagnosis (65, >65 years). Instructions: The nomogram yields the 10-year OS probability corresponding to a patient’s combination of covariates. Locate the patient’s tumour site and draw a line straight upward to the Points axis to determine the score associated with that site. Repeat the process for tumour size and mitotic index, sum the three resulting scores, and locate the sum on the Total Points axis. Then, on the basis of patient’s age at diagnosis (65 or >65 years), draw a line straight down to the corresponding 10-year OS axis to find OS probability. (Reproduced from Rossi et al.7 with permission from Lippincott Williams and Wilkins.)
1. Clinical information (which should be provided by the referring clinician): tumour location, clinical presentation, known syndromes, prior treatment (neoadjuvant therapy), metastatic or recurrent disease. 2. Macroscopic description: specimen type (including adjacent normal tissues, e.g., wedge resection of gastric wall), tumour size, cut surface, the presence of macroscopic necrosis, haemorrhage and/or tumour rupture, surgical margins. 3. Microscopic findings: tumour morphology (spindled, epithelioid or mixed) and any unusual features, mitoses Table 1
7.
GIST risk stratification schema as proposed by Joensuu60
Risk category
Very low risk Low risk Intermediate risk High risk
4. 5. 6.
Tumour size (cm)
Mitotic index (/50HPF)
Primary tumour site
5.0 2.1–5.0 5.1–10.0
5 5 >5 6–10 5 Any Any >10 >5 >5 5
Any Any Gastric Any Gastric Tumour rupture Any Any Any Non-gastric Non-gastric
8. 9.
(preferably expressed per 5 mm2, or state field diameter of the microscope used), necrosis, lymphovascular invasion, surgical margins, lymph node status (when included). Immunophenotype. Treatment effect (if present). Mutational analysis (where indicated, add a note to this effect). Risk stratification: to some extent which schema is employed will be based on local preference but until such time as one system is clearly shown to be superior, at least one of the recognised systems should be applied. We advocate Joensuu’s modification of the NIH criteria60 (see Table 1) and/or at least one of the nomograms referred to above6,7,11 (see Fig. 5, 6 and 7). AJCC (7th edition) staging parameters.59 Comments: if factors are identified which may indicate a syndrome such as Carney triad, Carney–Stratakis syndrome or familial GIST, these should be commented upon. Epithelioid GIST, especially those occurring in females under the age of 40, should be submitted for SDH immunohistochemistry and if this is negative, it is recommended that a comment be made to the effect that Carney–Stratakis syndrome or Carney triad should be considered and appropriate clinical surveillance be instituted.27
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THE CHANGING FACE OF GIST: IMPLICATIONS FOR PATHOLOGISTS
Gastric, rupture unknown
Non-gastric, rupture unknown
147
E-GIST, rupture unknown
Mitotic count
50
A
25 15 10 5 2
Mitotic count
50
D
B
0 Gastric with no rupture
C Non-gastric with no rupture
E-GIST with no rupture
25 15 10 5 2
E
0
F Non-gastric with rupture
Gastric with rupture
E-GIST with rupture
Mitotic count
50
G
25 15 10 5 2 0 0.1
2
0% 10% 20%
5 10 15 Tumour size (cm) 40%
60%
25
H
0.1
2
5 10 15 Tumour size (cm)
25
I
0.1
2
5 10 15 Tumour size (cm)
25
80% 90% 100%
Fig. 7 Contour maps for estimating the risk of GIST recurrence after surgery. The upper row maps are used when tumour rupture status is unknown (A–C), the middle row maps when the tumour has not ruptured (D–F), and the bottom row maps when tumour rupture has occurred (G–I). Red areas depict high risk, blue areas low risk, and white areas indicate lack of data. The percentages associated with each colour (key) indicate the probability of GIST recurrence within the first 10 years of follow-up after surgery. For example, the middle map of the far left column (D) shows that the 10-year risk of GIST recurrence of a patient diagnosed with a 10 cm gastric GIST with 5 mitoses per 50 high power fields (HPFs) of the microscope and no rupture is 20–40%. The 10-year risk associated with a similar tumour when the mitosis count is 10 per 50 HPFs increases to 40–60%. E-GIST, extragastrointestinal stromal tumour (arising outside the gastrointestinal tract). (Reproduced from Joensuu et al.11 with permission from Elsevier.)
Conflicts of interest and sources of funding: The authors state that there are no conflicts of interest to disclose. Address for correspondence: Dr C. Hemmings, SJOG Pathology, Level 5, Bendat Family Comprehensive Cancer Centre, 12 Salvado Rd, Subiaco, WA 6008, Australia. E-mail: [email protected]
8.
9.
References 1. Miettinen M, Corless C, Lasota J, et al. Gastrointestinal stromal tumours. In: Fletcher C, Bridge J, Hogendoorn C, Mertens F, editors. WHO Classification of Tumours of Soft Tissue and Bone. 4th ed. Lyon: IARC Press, 2013. 2. Agaimy A, Wunsch P, Hofstaedter F, et al. Minute gastric sclerosing stromal tumors (GIST tumorlets) are common in adults and frequently show c-KIT mutations. Am J Surg Pathol 2007; 31: 113–20. 3. Kawanowa K, Sakuma Y, Sakurai S, et al. High incidence of microscopic gastrointestinal stromal tumors in the stomach. Hum Pathol 2006; 37: 1527–35. 4. Fletcher C, Berman J, Corless C, et al. Diagnosis of gastrointestinal stromal tumors: A consensus approach. Hum Pathol 2002; 33: 459–65. 5. Miettinen M, Lasota J. Gastrointestinal stromal tumors: pathology and prognosis at different sites. Semin Diagn Pathol 2006; 23: 70–83. 6. Gold J, Gonen M, Gutierrez A, et al. Development and validation of a prognostic nomogram for recurrence-free survival after complete surgical resection of localised primary gastrointestinal stromal tumour: a retrospective analysis. Lancet Oncol 2009; 10: 1045–52. 7. Rossi S, Miceli R, Messerini L, et al. Natural history of imatinib-naive GISTs: a retrospective analysis of 929 cases with long-term follow-up and
10. 11. 12. 13.
14. 15. 16.
development of a survival nomogram based on mitotic index and size as continuous variables. Am J Surg Pathol 2011; 35: 1646–56. Stratakis C, Carney J. The triad of paragangliomas, gastric stromal tumours and pulmonary chondromas (Carney triad), and the dyad of paragangliomas and gastric stromal sarcomas (Carney-Stratakis syndrome): molecular genetics and clinical implications. J Intern Med 2009; 266: 43–52. Pasini B, McWhinney S, Bei T, 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; 16: 79–88. Lv A, Li Z, Tian X, et al. SKP2 high expression, KIT exon 11 deletions,;1; and gastrointestinal bleeding as predictors of poor prognosis in primary gastrointestinal stromal tumors. PLoS ONE 2013; 8: e62951. Joensuu H, Vehtari J, Nishida T, et al. Risk of recurrence of gastrointestinal stromal tumour after surgery: an analysis of pooled population-based cohorts. Lancet Oncol 2012; 13: 265–74. Miettinen M, Sobin L, Lasota J. Gastrointestinal stromal tumors presenting as omental masses – A clinicopathologic analysis of 95 cases. Am J Surg Pathol 2009; 33: 1267–75. Long K, Butrynski J, Blank S, et al. Primary extragastrointestinal stromal tumor of the pleura: report of a unique case with genetic confirmation. Am J Surg Pathol 2010; 34: 907–12. Irving J, Lerwill M, Young R. Gastrointestinal stromal tumors metastatic to the ovary: A report of five cases. Am J Surg Pathol 2005; 29: 920–6. Hughes B, Yip D, Goldstein D, et al. Cerebral relapse of metastatic gastrointestinal stromal tumor during treatment with imatinib mesylate: case report. BMC Cancer 2004; 4: 74. Jati A, Tatli S, Morgan J, et al. Imaging features of bone metastases in patients with gastrointestinal stromal tumors. Diagn Interv Radiol 2012; 18: 391–6.
Copyright © Royal College of pathologists of Australasia. Unauthorized reproduction of this article is prohibited.
148
HEMMINGS and YIP
17. Nilsson B, Bumming P, Meis-Kindblom J, et al. Gastrointestinal stromal tumors: the incidence, the prevalence, clinical course and prognostication in the preimatinib mesylate era: A population-based study in western Sweden. Cancer 2005; 103: 821–9. 18. Carney J, Sheps S, Go V, Gordon H. The triad of gastric leiomyosarcoma, functioning extra-adrenal paraganglioma and pulmonary chondroma. N Engl J Med 1977; 296: 1517–8. 19. Carney J, Stratakis C. Familial paraganglioma and gastric stromal sarcoma: a new syndrome distinct from Carney triad. Am J Med Genet 2002; 108: 132–9. 20. McWhinney S, Pasini B, Stratakis C. Familial gastrointestinal stromal tumors and germ-line mutations. N Engl J Med 2007; 357: 1054–6. 21. Miettinen M, Killian J, Wang Z, et al. Immunohistochemical loss of succinate dehydrogenase subunit A (SDHA) in gastrointestinal stromal tumors (GISTs) signals SDHA germline mutation. Am J Surg Pathol 2013; 37: 234–40. 22. Dwight T, Benn D, Clarkson A, et al. Loss of SDHA expression identifies SHDA mutations in succinate dehydrogenase-deficient gastrointestinal stromal tumors. Am J Surg Pathol 2013; 37: 226–33. 23. Postow M, Robson M. Inherited gastrointestinal stromal tumor syndromes: mutations, clinical features, and therapeutic implications. Clin Sarcoma Res 2012; 2: 16. 24. Matyakhina L, Bei T, McWhinney S, et al. Genetics of Carney triad: Recurrent losses at chromosome 1 but lack of germline mutations in genes associated with paragangliomas and gastrointestinal stromal tumors. J Clin Endocrinol Metab 2007; 92: 2938–43. 25. Miettinen M, Wang Z, Sarlomo-Rikala M, et al. Succinate dehydrogenasedeficient GISTs: A clinicopathologic, immunohistochemical, and molecular genetic study of 66 gastric GISTs with predilection to young age. Am J Surg Pathol 2011; 35: 1712–21. 26. Wagner A, Remillard S, Zhang Y, et al. Loss of expression of SDHA predicts SHDA mutations in gastrointestinal stromal tumors. Mod Pathol 2013; 26: 289–94. 27. Gaal J, Stratakis C, Carney J, et al. SDHB immunohistochemistry: A useful took in the diagnosis of Carney-Stratakis and Carney triad gastrointestinal stromal tumors. Mod Pathol 2011; 24: 147–51. 28. Chompret A, Kannengiesser C, Barrois M, et al. PDGFRA germline mutation in a family with multiple cases of gastrointestinal stromal tumor. Gastroenterology 2004; 126: 318–21. 29. Neuhann T, Mansmann V, Merkelbach-Bruse S, et al. A novel germline mutation (p.L576P) in a family presenting with juvenile onset of multiple gastrointestinal stromal tumors, skin hyperpigmentations, and esophageal stenosis. Am J Surg Pathol 2013; 37: 898–905. 30. Carballo M, Roig I, Aguilar F, et al. Novel c-KIT germline mutation in a family with gastrointestinal stromal tumors and cutaneous hyperpigmentation. Am J Med Genet A 2005; 132: 361–4. 31. Maeyama H, Hidaka E, Ota H, et al. Familial gastrointestinal stromal tumor with hyperpigmentation: association with a germline mutation of the c-kit gene. Gastroenterology 2001; 120: 210–5. 32. Miettinen M, Lasota J. Gastrointestinal stromal tumors: Review on morphology, molecular pathology, prognosis and differential diagnosis. Arch Pathol Lab Med 2006; 130: 1466–78. 33. Mussi C, Schildhaus H, Gronchi A, et al. Therapeutic consequences from molecular biology for gastrointestinal stromal tumor patients affected by neurofibromatosis type I. Clin Cancer Res 2008; 14: 4550–5. 34. Wang J, Lasota J, Miettinen M. Succinate dehydrogenase subunit B (SDHB) is expressed in neurofibromatosis 1-associated gastrointestinal stromal tumors (GISTs): Implications for the SDHB expression based classification of GISTs. J Cancer 2011; 16: 90–3. 35. Maertens O, Prenen H, Debiec-Rychter M, et al. Molecular pathogenesis of multiple gastrointestinal stromal tumors in NF1 patients. Hum Mol Genet 2006; 15: 1015–23. 36. Ponti G, Luppi G, Martorana D, et al. Gastrointestinal stromal tumor and other primary metachronous or synchronous neoplasms as a suspicion criterion for syndromic setting. Oncol Reports 2012; 23: 437–44. 37. Miettinen M, Kraszewska E, Sobin L, Lasota J. A nonrandom association between gastrointestinal stromal tumors and myeloid leukaemia. Cancer 2008; 112: 645–9. 38. Hanson J, Trent J, Yang D, Cooper K. Small-intestinal rhabdoid gastrointestinal stromal tumor (GIST): Mutation analysis and clinical implications of a rare morphological variant. Int J Surg Pathol 2011; 19: 653–7. 39. Antonescu C, Romeo S, Zhang L, et al. Dedifferentiation in gastrointestinal stromal tumor to an anaplastic KIT-negative phenotype: a diagnostic pitfall: morphologic and molecular characterization of 8 cases occurring either de novo or after imatinib therapy. Am J Surg Pathol 2013; 37: 385–92. 40. Pauwels P, Debiec-Rychter M, Stul M, et al. Changing phenotype of gastrointestinal stromal tumours under imatinib mesylate treatment: A potential diagnostic pitfall. Histopathology 2005; 47: 41–7. 41. Koh Y, Lee H, Ohn D, et al. The lack of CD34 expression in gastrointestinal stromal tumors is related to cystic degeneration following imatinib use. Jpn J Clin Oncol 2012; 42: 1020–7.
Pathology (2014), 46(2), February
42. Mearadji A, den Bakker M, van Geel A, et al. Decrease of CD117 expression as possible prognostic marker for recurrence in the resected specimen after imatinib treatment in patients with initially unresectable gastrointestinal stromal tumors: A clinicopathological analysis. Anticancer Drugs 2008; 19: 607–12. 43. Rutkowski P, Nowecki Z, Nyckowski P, et al. Surgical treatment of patients with initially inoperable and/or metastatic gastrointestinal stromal tumors (GIST) during therapy with imatinib mesylate. J Surg Oncol 2006; 93: 304–11. 44. Liegl B, Hornick J, Antonescu C, et al. Rhabdomyosarcomatous differentiation in gastrointestinal stromal tumors after tyrosine kinase inhibitor therapy: A novel form of tumor progression. Am J Surg Pathol 2009; 33: 218–26. 45. Agaram N, Besmer P, Wong G, et al. Pathologic and molecular heterogeneity in imatinib-stable or imatinib-responsive gastrointestinal stromal tumors. Clin Cancer Res 2007; 13: 170–81. 46. West R, Corless C, Chen X, et al. The novel marker, DOG1, is expressed ubiquitously in gastrointestinal stromal tumors irrespective of KIT or PDGFRA mutation status. Am J Pathol 2004; 165: 107–13. 47. Liegl B, Hornick J, Corless C, Fletcher C. Monoclonal antibody DOG1.1 shows higher sensitivity than KIT in the diagnosis of gastrointestinal stromal tumors, including unusual subtypes. Am J Surg Pathol 2009; 33: 437–46. 48. Parfitt J, Rodriguez-Justo M, Feakings R, Novelli M. Gastrointestinal Kaposi’s sarcoma: CD117 expression and the potential for misdiagnosis as gastrointestinal stromal tumour. Histopathology 2008; 52: 816–23. 49. Malik L, Hemmings C, Beshay V, et al. Metastatic gastrointestinal stromal tumour of the ileum with dual primary c-KIT missence (sic) mutations. Pathology 2013; 45: 604–6. 50. Casali P, Fumagalli E, Gronchi A. Adjuvant therapy of gastrointestinal stormal tumors (GIST). Curr Treat Options Oncol 2013; 13: 277–84. 51. Gastrointestinal Stromal Tumor Meta-Analysis Group (MetaGIST)Comparison of two doses of imatinib for the treatment of unresectable or metastatic gastrointestinal stromal tumors: A meta-analysis of 1,640 patients. J Clin Oncol 2010; 28: 1247–53. 52. Maier J, Lange T, Kerle I, et al. Detection of mutant free circulating tumor DNA in the plasma of patients with gastrointestinal stromal tumor harbouring activating mutations of CKIT or PDGFRA. Clin Cancer Res 2013; 19: 4854–67. 53. Braconi C, Bracci R, Bearzi I, et al. Insulin-like growth factor (IGF) 1 and 2 help to predict disease outcome in GIST patients. Ann Oncol 2008; 19: 1293–8. 54. Rink L, Godwin A. Clinical and molecular characteristics of gastrointestinal stromal tumor in the pediatric and young adult population. Curr Oncol Rep 2009; 11: 314–21. 55. Chou A, Chen J, Clarkson A, et al. Succinate dehydrogenase-deficient GISTs are characterized by IGF1R overexpression. Mod Pathol 2012; 25: 1307–13. 56. Lasota J, Wang Z, Kim S, et al. Expression of the receptor for type I insulinlike growth factor (IGF1R) in gastrointestinal stromal tumors: An immunohistochemical study of 1078 cases with diagnostic and therapeutic implications. Am J Surg Pathol 2013; 37: 114–9. 57. Tarn C, Rink L, Merkel E, et al. Insulin-like growth factor 1 receptor is a potential therapeutic target for gastrointestinal stromal tumors. Proc Natl Acad Sci USA 2008; 105: 8387–92. 58. Agaram N, Wong G, Guo T, et al. Novel V600E BRAF mutations in imatinib-naı¨ve and imatinib-resistant gastrointestinal stromal tumours. Genes Chromosomes Cancer 2008; 47: 853–9. 59. Edge S, Byrd D, Compton C, et al. Cancer Staging Handbook. 7th ed. New York: Springer, 2010. Chapter 16, Gastrointestinal stromal tumor. 60. Joensuu H. Risk stratification of patients diagnosed with gastrointestinal stromal tumor. Hum Pathol 2008; 39: 1411–9. 61. Takahashi T, Nakajima K, Nishitani A, et al. An enhanced risk-group stratification system for more practical prognostication of clinically malignant gastrointestinal stromal tumors. Int J Clin Oncol 2007; 12: 369–74. 62. Rutkowski P, Bylina E, Wozniak A, et al. Validation of the Joensuu risk criteria for primary resectable gastrointestinal stromal tumour – The impact of tumour rupture on patient outcomes. Eur J Surg Oncol 2011; 37: 890–6. 63. Sabah M, Cummins R, Leader M, Kay E. Altered expression of cell cycle regulatory proteins in gastrointestinal stromal tumors: Markers with potential prognostic implications. Hum Pathol 2006; 37: 648–55. 64. Steinert D, Oyarzo M, Wang X, et al. Expresion of Bcl-2 in gastrointestinal stromal tumors: correlation with progression-free survival in 81 patients treated with imatinib mesylate. Cancer 2006; 106: 1617–23. 65. Montgomery E, Abraham S, Fisher C, et al. CD44 loss in gastric stromal tumors as a prognostic marker. Am J Surg Pathol 2004; 28: 168–77. 66. Wong N, Young R, Malcomson R, et al. Prognostic indicators for gastrointestinal stromal tumours: A clinicopathological and immunohistochemical study of 108 resected cases of the stomach. Histopathol 2003; 43: 118– 26.
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