The immunohistochemical hallmarks of gastrointestinal stromal tumors (GISTs) are positivity for CD117 (c-kit) and CD34; however, CD117 is not specific for GISTs, and the list of CD117+ tumors/tissues is increasing. Also, MDM2 is known to be amplified in several types of mesenchymal tumors, including liposarcoma.
Methods
We report a spindle cell sarcoma arising in the mediastinum that morphologically and immunohistochemically mimicked GIST to illustrate the potential diagnostic pitfalls of ancillary studies in sarcoma and their appropriate use in conjunction with clinical content. Clinical information was obtained from electronic medical databases. Cytological, histological, and ancillary studies were retrieved from the archives of the Department of Anatomic Pathology at Moffitt Cancer Center. Literature of the last 20 years was reviewed. The role of biomarkers and their molecular testing in the prognosis and prediction of GIST is also discussed.
Results
A 75-year-old woman with a history of well-differentiated liposarcoma of the trunk/inguinal canal 5 years earlier developed a 5.5-cm heterogeneously enhancing mediastinal mass by computed tomography. Fine-needle aspiration biopsy revealed spindle cells with moderate pleomorphism and immunohistochemically reactive to CD117 and CD34 suggestive of GIST, but the clinical picture was unusual for GIST. Mutational analyses for KIT and platelet-derived growth factor receptor alpha (PDGFRa) were negative; DOG1 was not immunoactive, and this was believed to rule out GIST. An additional study of MDM2 by fluorescent in situ hybridization was positive, suggesting that this tumor was a dedifferentiated liposarcoma vs a spindle cell sarcoma not otherwise specified.
Conclusions
CD117+/CD34+ sarcoma is not diagnostic for GIST. KIT and PDGFRα mutational analyses are important in confirming a diagnosis of GIST and predicting its response to imatinib therapy. MDM2+ sarcoma is not diagnostic for liposarcoma. Although MDM2 is almost always positive in well-differentiated liposarcoma, which is useful in differentiating benign from atypical/well-differentiated lipomatous tumor, it should not be used in differentiating liposarcoma from other sarcomas.
References
1.
RosaiJ.. Special techniques in surgical pathology. In: RosaiJ., ed. Rosai and Ackerman's Surgical Pathology Review. Vol 1. 9th ed.New York, NY: Mosby; 2004.
2.
BuiM.M., SmithP., AgrestaS.V.. Practical issues of intraoperative frozen section diagnosis of bone and soft tissue lesions.Cancer Control.2008; 15(1): 7–12.
3.
FülöpE., MarcuS., MilutinD.. Gastrointestinal stromal tumors: review on morphology, diagnosis and management.Rom J Morphol Embryol.2009; 50(3): 319–326.
4.
FletcherC.D.M., UnniK., MertensF., eds. World Health Organization Classification of Tumours Pathology and Genetics of Tumours of Soft Tissue and Bone.Lyon, France: IARC Press; 2002.
5.
Llenas-GarcíaJ., Guerra-ValesJ.M., MorenoA.. Primary extragas-trointestinal stromal tumors in the omentum and mesentery: a clinicopathological and immunohistochemical study.Hepatogastroenterology.2008; 55(84): 1002–1005.
6.
ReithJ.D., GoldblumJ.R., LylesR.H.. Extragastrointestinal (soft tissue) stromal tumors: an analysis of 48 cases with emphasis on histologic predictors of outcome.Mod Pathol.2000; 13(5): 577–585.
7.
HirotaS., NishidaT., IsozakiK.. Gain-of-function mutation at the extracellular domain of KIT in gastrointestinal stromal tumours.J Pathol.2001; 193(4): 505–510.
8.
NakaharaM., IsozakiK., HirotaS.. A novel gain-of-function mutation of c-kit gene in gastrointestinal stromal tumors.Gastroenterology.1998; 115(5): 1090–1095.
9.
SircarK., HewlettB.R., HuizingaJ.D.. Interstitial cells of Cajal as precursors of gastrointestinal stromal tumors.Am J Surg Pathol.1999; 23(4): 377–389.
10.
TortellaB.J., MatthewsJ.B., AntonioliD.A.. Gastric autonomic nerve (GAN) tumor and extra-adrenal paraganglioma in Carney's triad: a common origin.Ann Surg.1987; 205(3): 221–225.
MiettinenM., LasotaJ., SobinL.H.. Gastrointestinal stromal tumors of the stomach in children and young adults: a clinicopathologic, immunohistochemical, and molecular genetic study of 44 cases with long-term follow-up and review of the literature.Am J Surg Pathol.2005; 29(10): 1373–1381.
13.
PrakashS., SarranL., SocciN.. 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; 27(4): 179–187.
14.
BatesA.W., FeakinsR.M., ScheimbergI.. Congenital gastrointestinal stromal tumour is morphologically indistinguishable from the adult form, but does not express CD117 and carries a favourable prognosis.Histopathology.2000; 37(4): 316–322.
15.
Graadt van RoggenJ.F., van VelthuysenM.L., HogendoornP.C.. The histopathological differential diagnosis of gastrointestinal stromal tumours.J Clin Pathol.2001; 54(2): 96–102.
16.
ArberD.A., TamayoR., WeissL.M.. Paraffin section detection of the c-kit gene product (CD117) in human tissues: value in the diagnosis of mast cell disorders.Hum Pathol.1998; 29(5): 498–504.
17.
GibsonP.C., CooperK.. CD117 (KIT): a diverse protein with selective applications in surgical pathology.Adv Anat Pathol.2002; 9(1): 65–69.
18.
PelleM.T., ParcY., MourraN.. c-Kit expression in spindle cell melanoma: a diagnostic pitfall in anorectal biopsy.Arch Pathol Lab Med.2009; 133(8): 1189–1191.
MiliarasD., KarasavvidouF., PapanikolaouA.. KIT expression in fetal, normal adult, and neoplastic renal tissues.J Clin Pathol.2004; 57(5): 463–466.
21.
EspinosaI., LeeC.H., KimM.K.. A novel monoclonal antibody against DOG1 is a sensitive and specific marker for gastrointestinal stromal tumors.Am J Surg Pathol.2008; 32(2): 210–218.
22.
KoayM.H., GohY.W., IacopettaB.. Gastrointestinal stromal tumours (GISTs): a clinicopathological and molecular study of 66 cases.Pathology.2005; 37(1): 22–31.
23.
MiettinenM., LasotaJ.. Gastrointestinal stromal tumors: review on morphology, molecular pathology, prognosis, and differential diagnosis.Arch Pathol Lab Med.2006; 130(10): 1466–1478.
24.
LasotaJ., CorlessC.L., HeinrichM.C.. Clinicopathologic profile of gastrointestinal stromal tumors (GISTs) with primary KIT exon 13 or exon 17 mutations: a multicenter study on 54 cases.Mod Pathol.2008; 21(4): 476–484.
25.
LongleyB.J., RegueraM.J., MaY.. Classes of c-KIT activating mutations: proposed mechanisms of action and implications for disease classification and therapy.Leuk Res.2001; 25(7): 571–576.
26.
CorlessC.L., SchroederA., GriffithD.. PDGFRA mutations in gastrointestinal stromal tumors: frequency, spectrum and in vitro sensitivity to imatinib.J Clin Oncol.2005; 23(23): 5357–5364.
27.
LasotaJ., StachuraJ., MiettinenM.. GISTs with PDGFRA exon 14 mutations represent subset of clinically favorable gastric tumors with epithelioid morphology.Lab Invest.2006; 86(1): 94–100.
28.
van de RijnM., RouseR.V.. CD34: a review.Appl Immunohistochem.1994; 2: 71–80.
29.
WeissS.W., NickoloffB.J.. CD-34 is expressed by a distinctive cell population in peripheral nerve, nerve sheath tumors, and related lesions.Am J Surg Pathol.1993; 17(10): 1039–1045.
30.
van de RijnM., LombardC.M., RouseR.V.. Expression of CD34 by solitary fibrous tumors of the pleura, mediastinum, and lung.Am J Surg Pathol.1994; 18(8): 814–820.
31.
SusterS., FisherC.. Immunoreactivity for the human hematopoietic progenitor cell antigen (CD34) in lipomatous tumors.Am J Surg Pathol.1997; 21(2): 195–200.
32.
TempletonS.F., SolomonA.R.Jr. Spindle cell lipoma is strongly CD34 positive: an immunohistochemical study.J Cutan Pathol.1996; 23(6): 546–550.
33.
SilvermanJ.S., TamsenA.. Fibrohistiocytic differentiation in subcuta-neous fatty tumors: study of spindle cell, pleomorphic, myxoid, and atypical lipoma and dedifferentiated liposarcoma cases composed in part of CD34+ fibroblasts and FXIIIa+ histiocytes.J Cutan Pathol.1997; 24(8): 484–493.
34.
WestR.B., CorlessC.L., ChenX.. The novel marker, DOG1, is expressed ubiquitously in gastrointestinal stromal tumors irrespective of KIT or PDGFRA mutation status.Am J Pathol.2004; 165(1): 107–113.
35.
NovelliM., RossiS., Rodriguez-JustoM.. DOG1 and CD117 are the antibodies of choice in the diagnosis of gastrointestinal stromal tumours.Histopathology.2010; 57(2): 259–270.
36.
LieglB., HornickJ.L., CorlessC.L.. 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(3): 437–446.
37.
WeissS.W., RaoV.K.. Well-differentiated liposarcoma (atypical lipoma) of deep soft tissue of the extremities, retroperitoneum, and miscellaneous sites: a follow-up study of 92 cases with analysis of the incidence of “dedifferentiation”.Am J Surg Pathol.1992; 16(11): 1051–1058.
38.
Dei TosA.P., MentzelT., NewmanP.L.. Spindle cell liposarcoma, a hitherto unrecognized variant of liposarcoma: analysis of six cases.Am J Surg Pathol.1994; 18(9): 913–921.
39.
EvansH.L.. Atypical lipomatous tumor, its variants, and its combined forms: a study of 61 cases, with a minimum follow-up of 10 years.Am J Surg Pathol.2007; 31(1): 1–14.
40.
Meis-KindblomJ.M., SjögrenH., KindblomL.G.. Cytogenetic and molecular genetic analyses of liposarcoma and its soft tissue simulators: recognition of new variants and differential diagnosis.Virchows Arch.2001; 439(2): 141–151.
41.
SandbergA.A.. Updates on the cytogenetics and molecular genetics of bone and soft tissue tumors: liposarcoma.Cancer Genet Cytogenet.2004; 155(1): 1–24.
42.
PedeutourF., ForusA., CoindreJ.M.. Structure of the supernumerary ring and giant rod chromosomes in adipose tissue tumors.Genes Chromosomes Cancer.1999; 24(1): 30–41.
43.
ItalianoA., BianchiniL., KeslairF.. HMGA2 is the partner of MDM2 in well-differentiated and dedifferentiated liposarcomas whereas CDK4 belongs to a distinct inconsistent amplicon.Int J Cancer.2008; 122(10): 2233–2241.
44.
BinhM.B., Sastre-GarauX., GuillouL.. MDM2 and CDK4 immunostainings are useful adjuncts in diagnosing well-differentiated and dedifferentiated liposarcoma subtypes: a comparative analysis of 559 soft tissue neoplasms with genetic data.Am J Surg Pathol.2005; 29(10): 1340–1347.
45.
DaugaardS., ChristensenL.H., HøgdallE.. Markers aiding the diagnosis of chondroid tumors: an immunohistochemical study including osteonectin, bcl-2, cox-2, actin, calponin, D2-40 (podoplanin), mdm-2, CD117 (c-kit), and YKL-40.APMIS.2009; 117(7): 518–525.
46.
Bode-LesniewskaB., ZhaoJ., SpeelE.J.. Gains of 12q13-14 and overexpression of mdm2 are frequent findings in intimal sarcomas of the pulmonary artery.Virchows Arch.2001; 438(1): 57–65.
