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CD117

Characteristics

CD117 is a 145-160 kDa cell membrane protein encoded by the c-kit proto-oncogene (chromosome 4q11-12). The protein is a type III tyrosine kinase growth factor receptor* for stem cell factor (SCF), also known as mast cell growth factor. CD117 is required for the development and growth of a large number of cells expressing this protein.

CD117 is expressed in mast cells (Fig. 1A), melanocytes and interstitial cells of Cajal (ICC)** (Fig. 1B). The cells (particularly the mast cells) show a strong membrane as well as cytoplasmic staining. CD117 moreover is expressed in various epithelia (breast, sweat glands and salivary glands, renal tubular cells, thyroid follicular cells), usually showing a weaker, cytoplasmic reaction. CD117 is also demonstrated in testicular and ovarian interstitial cells, in neurons of the central nervous system (cerebellum, hippocampus, and dorsal horn of the spinal cord), and in immature myeloid cells (at low levels, approximately 70% of CD34+ cells in normal bone marrow as demonstrated by flow cytometry). Finally CD117 is detected in trophoblastic cells, foetal (but not mature) endothelial cells and foetal (but not mature) basal cells of the skin. CD117 does not occur in smooth muscle cells.

* Family of transmembrane proteins essential for the regulation of cell growth and maintenance. When a growth factor is bound to its receptor, the latter is phosphorylated and begins a cascade of intracytoplasmic signals.

** Cells involved in the generation of electrical pacemaker activity for gastrointestinal motility. The cells are considered to be the origin of gastrointestinal stromal tumours.

 

Neoplasms

The following neoplasms express CD117 in more than 90% of the cases*: Gastrointestinal stromal tumour (GIST) (Fig. 2A), mast cell neoplasms, malignant melanoma (however, the expression of CD117 is lost during progression and metastasising) (Fig. 2B), seminoma/dysgerminoma (Fig, 2C) and intratubular germ cell neoplasia, endometrial carcinoma, follicular and papillary thyroid carcinoma, Merkel cell carcinoma, cylindroma, malignant glioma, and angiomyolipoma.

The following express CD117 in 50-90% of the cases: adenocarcinomas of lung and pancreas, hepatocellular carcinoma, squamous cell carcinoma of esophagus and lung, transitiocellular carcinoma, endodermal sinus tumour, neuroblastoma, osteogenic sarcoma, fibromatosis, Wilms' tumour, and epithelioid sarcoma.

The following express CD117 in 10-50% of the cases: adenocarcinomas of breast, salivary glands, ovary, colorectum and prostate, small cell carcinoma, embryonal carcinoma, malignant mesothelioma, Ewing sarcoma, synovial sarcoma, chondrosarcoma, angiosarcoma and Kaposi sarcoma, malignant phyllodes tumour, perineurioma, acute myeloid leukaemia and subtypes of malignant lymphomas.

The staining pattern in strongly CD117 positive neoplasms is generally diffuse/granular cytoplasmic with membrane accentuation. Occasionally, a perinuclear staining is seen. In neoplasms with a weaker expression, this is mostly cytoplasmic.

CD117 is not detected in smooth muscle tumours (Fig. 2D), rhabdomyosarcoma, schwannoma (except for the melanotic subtype), peripheral nerve sheath tumour, endometrial stromal sarcoma, desmoplastic small cell tumour, and solitary fibrous tumour.

* The grouping of neoplasms based on the proportion in which a certain epitope is expressed should be considered as a guideline only as it is based on metaanalyzes of studies using different study materials and methodologies (antibodies, epitope retrieval methods etc.)

 

Application

CD117 is of great importance for the classification of mesenchymal tumours of the gastrointestinal tract (including the mesentery). A newly developed molecule, STI-571 (Gleveec), binds selectively to CD117 resulting in inhibition of tyrosine phosphorylation. This molecule has shown effective in the treatment of GIST, enhancing the importance of using the CD117 antibody for tumour classification and section for therapy.

In the immunohistochemical classification of gastrointestinal tumours, the antibody panel should include CD34, S-100 protein, alpha-smooth muscle actin, and desmin.

CD117 may also be used for classification of germinal cell tumours, as seminoma/dysgerminoma stains in the majority of cases, showing a strong membranous staining, while embryonal carcinoma stains in a small proportion of cases, with a weaker, membranous reaction. An panel for distinguishing seminoma from embryonal carcinoma should include CD30.

Also in the identification of mast cell neoplasms CD117 has a potential.

 

Visualization

pAb CD117 from DakoCytomation (A4502) has shown well functioning after HIER (particularly in a high pH buffer), see Retrieval: CD117. The Ab dilution must be carefully calibrated in order to avoid nonspecific staining of, e.g., smooth muscle cells. Some variation in Ab avidity between different lots has been seen. Therefore, the calibration must be carried out for each lot.

Control tissue: Appendix is appropriate; the Cajal cells should be intensively labelled without any staining of the smooth muscle cells and no or minimal staining of the enterocytes.
 

Assessments

Run 4 2001
Run 7 2003

Run 14 2005
Run 21 2007
Run 26 2009

 

Selected references

Arber et al: 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.

Ashman LK. The biology of stem cell factor and its receptor C-kit. Int J Biochem Cell Biol. 1999 Oct;31(10):1037-51. Review.

Ashman LK, Cambareri AC, To LB, Levinsky RJ, Juttner CA. Expression of the YB5.B8 antigen (c-kit proto-oncogene product) in normal human bone marrow. Blood. 1991 Jul 1;78(1):30-7.

Berghini et al: Germline mutation in the juxtamembrane domain of the c-kit gene in a family with gastrointestinal stromal tumors and urticaria pigmentosa. Cancer, 2001;92(3):657-62.

Chen et al: CD 34, CD 117 and actin expression in phyllodes tumour of the breast. J Surg Res 2000;94(2):84-91.

Graadt van Roggen et al: The histopathologic differential diagnosis of gastrointestinal stromal tumours. J Clin Pathol 2001; 54(2):96-102.

Fletcher CD, Berman JJ, Corless C, Gorstein F, Lasota J, Longley BJ, Miettinen M, O'Leary TJ, Remotti H, Rubin BP, Shmookler B, Sobin LH, Weiss SW. Diagnosis of gastrointestinal stromal tumours: A consensus approach. Hum Pathol. 2002 May;33(5):459-65. Review.

Gibson PC, Cooper K. CD117 (KIT): a diverse protein with selective applications in surgical pathology. Adv Anat Pathol. 2002 Jan;9(1):65-9. Review.

Hirota et al: Gain-of-function mutation of c-kit in human gastrointestinal stromal tumours. Science 1998;279:577-580.

Hornick JL, Fletcher CD. Immunohistochemical staining for KIT (CD117) in soft tissue sarcomas is very limited in distribution. Am J Clin Pathol. 2002 Feb;117(2):188-93.

Joensuu H, Fletcher C, Dimitrijevic S, Silberman S, Roberts P, Demetri G. Management of malignant gastrointestinal stromal tumours.Lancet Oncol. 2002 Nov;3(11):655-64. Review.

Kindblom LG, Remotti HE, Aldenborg F, Meis-Kindblom JM. Gastrointestinal pacemaker cell tumour (GIPACT): gastrointestinal stromal tumours show phenotypic characteristics of the interstitial cells of Cajal. Am J Pathol. 1998 May;152(5):1259-69.

Lammie A, Drobnjak M, Gerald W, Saad A, Cote R, Cordon-Cardo C. Expression of c-kit and kit ligand proteins in normal human tissues. J Histochem Cytochem. 1994 Nov;42(11):1417-25.

Lasota J, Carlson JA, Miettinen M. Spindle cell tumour of urinary bladder serosa with phenotypic and genotypic
features of gastrointestinal stromal tumour. Arch Pathol Lab Med. 2000 Jun;124(6):894-7.
Leroy X, Augusto D, Leteurtre E, Gosselin B. CD30 and CD117 (c-kit) used in combination are useful for distinguishing
embryonal carcinoma from seminoma. J Histochem Cytochem. 2002 Feb;50(2):283-5.

Miettinen M, Lasota J. Gastrointestinal stromal tumors--definition, clinical, histological, immunohistochemical, and molecular genetic features and differential diagnosis. Virchows Arch. 2001 Jan;438(1):1-12. Review.

Miettinen M, Majidi M, Lasota J. Pathology and diagnostic criteria of gastrointestinal stromal tumours (GISTs): a
review. Eur J Cancer. 2002 Sep;38 Suppl 5:S39-51.

Miettinen et al: KIT expression in angiosarcomas and fetal endothelial cells: lack of mutations of exon 11 and exon 17 of C-kit. Mod Pathol 2000;13(5):536-41.

Montone et al: Proto-oncogene c-kit expression in malignant melanoma: protein loss with tumour progression. Mod Pathol 1997; 10(9):939-44.

Reith et al: Extragastrointestinal (soft tissue) stromal tumours: an analysis of 48 cases with emphasis on histologic predictors and outcome. Mod Pathol 2000;13(5):577-85.

Sarlomo Rikala et al: CD 117: a sensitive marker for gastrointestinal stromal tumours that is more specific than CD 34. Mod Pathol 1998;11(8):728-34.

Seidal and Edvardsson: Expression of c-kit (CD117) and Ki-67 provides information of the possible cell of origin and clinical course in gastrointestinal stromal tumours. Histopathol 1999; 34:416-24.

Wardelmann E, Neidt I, Bierhoff E, Speidel N, Manegold C, Fischer HP, Pfeifer U, Pietsch T. c-kit mutations in gastrointestinal stromal tumours occur preferentially in the spindle rather than in the epithelioid cell variant. Mod Pathol. 2002 Feb;15(2):125-36.

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Last update 27-05-2009