CD117 (c-kit proto-oncogene)

The c-kit proto-oncogene codes for a 145 to 160 kDa type III transmembrane tyrosine kinase receptor protein, structurally and functionally closely related to platelet-derived growth factor and macrophage colony stimulating factor. The gene has been mapped to chromosome 4q11-12. The protein product, KIT, is the receptor for stem cell factor (mast cell growth factor). The ligand is an early haemopoietic growth factor, which is also required for the development of germ cells and melanocytes2. Loss of gene function during embryogenesis results in white spotting in mice and humans. The c-kit proto-oncogene is the cellular counterpart of the transforming gene of the Hardy-Zuckerman feline sarcoma virus19. There is homology to PDGF and colony stimulating factor19. Ligand binding results in dimerisation and phosphorylation of specific tyrosine residues. These phosphorylated sites in turn act as docking sites for signal transduction molecules , which themselves become phosphorylated and are often themselves kinases19.

The antisera available to date are polyclonal and are effective on paraffin-embedded tissue11.

The tyrosine kinase inhibitor STI-571 binds to the ATP enzymatic binding pocket of the tyrosine kinases c-abl, PDGF and c-kit. It is used to inhibit c-abl for the treatment of CML. There are results from Phase I and II trials that indicate that the tyrosine kinase inhibitor STI-571, by inhibiting c-kit, may be highly efficacious in the treatment of GISTs5. There is, as yet, no data to support a role for STI-571 in the treatment of other solid tumours which may express strong CD117 positivity (adenoid cystic carcinoma, seminoma, small cell lung carcinoma)6. STI-571 is likely to be less efficacious in tumours that have a mutation in exon 17 at codon 816, replacing aspartate with valine and so modifying the the tyrosine kinase binding pocket19.

Immunohistochemical expression

Normal tissues2:

Organ	tissue	nature of staining
general	mast cells	strong, membrane and cytoplasmic8
general	endothelium	weak, cytoplasmic
brain	glial cell, Purkinje cells	moderate, cytoplasmic
breast	ductal epithelium
stomach	parietal cells
kidney	renal tubules	moderate in proximal and weak in distal tubules, cytoplasmic, loop of Henle moderate, collecting ducts negative13
ovary	stroma and follicles	moderate, cytoplasmic
	oocytes	moderate to strong, cytoplasm and membrane
	corpus luteum	weak, cytoplasmic
testis	seminiferous tubules, germ cells	moderate to strong, cytoplasm and membrane
skin	melanocytes	moderate, cytoplasm10
	immature Langerhans' cells	positive10
	epidermal basal cells	positive8,10
gallbladder	epithelium	weak, cytoplasm
bladder	mucosa
prostate	some basal cells
thyroid	follicle epithelium
eye	cornea and retina	positivity reported
salivary gland	ducts and acinar cells
adrenal	medulla
small intestinal mucosa8	none
colonic mucosa8
liver
pancreas8
lymph node
peripheral nervous system8
endocervical glandular epithelium8
myometrium

Tumours:

80-100% of gastrointestinal stromal tumours1,4
melanomas5
some germ cell tumours5
some cases of AML
some dermatofibromas, angiosarcomas and Ewing's tumours5
An abstract reports positivity in 18% of a range of sarcomas and consistent positivity in synovial sarcoma9
There are conflicting reports of positivity in desmoid tumours5
The paper summarised below examined a large range of tumours.(cases are considered positive if more than 5% of the tumour cells stain)2:

	strong
mast cell disease	11/11(all cases strong staining)2, 22/227
breast, invasive ductal carcinoma	19/472, 1/921
breast, lobular carcinoma	0/32
breast, DCIS	2/2(staining weak)2
lung, adenocarcinoma	26/342, 1/821
non small cell carcinoma of the lung	8/1443
lung, squamous cell carcinoma	15/21(weak staining in 15 cases)2, 1/521
lung, small cell carcinoma	6/72, 45/1233, 23/4019, 2/321
lung, carcinoid tumour	1/121
lung, low grade mucoepidermoid carcinoma	1/121
lung, adenoid cystic carcinoma	1/121
extrapulmonary small cell carcinoma	4/42
lung, clear cell carcinoma	0/12
mesothelioma	13/502
salivary gland, oncocytoma	2/221
salivary gland, Warthin tumour	1/221
salivary gland, adenoid cystic carcinoma	6/621
oesophagus, squamous cell carcinoma	4/5(weak in 4 cases)2
stomach, adenocarcinoma	0/12
duodenum, adenocarcinoma	1/421
colon, adenoma	2/321
colon, adenocarcinoma	7/302
pancreas, adenocarcinoma	8/142, 2/921
pancreas, islet cell tumour	1/1(weak)2
liver, hepatocellular carcinoma	2/3(weak)2
bladder, transitional cell carcinoma	15/242, 1/421, 3/1421
bladder, adenocarcinoma	1/321
prostate, adenocarcinoma	6/29(weak)2
renal cell carcinoma NOS	0/282
conventional renal cell carcinoma	2/1313, 1/421
papillary renal cell carcinoma	2/713, 1/421
chromophobe renal cell carcinoma	4/713, 11/1118, 4/421
renal nephroblastoma	0/613
renal oncocytoma	7/713, 12/1218, 2/221
mesoblastic nephroma	2/213
renal neuroblastoma	1/221
angiomyolipoma	2/413, 2120
cervix, adenocarcinoma	1/521
endometrium, hyperplasia	2/2(weak)2
endometrium, adenocarcinoma	8/82, 2/721
ovary, serous carcinoma	14/162
ovary, clear cell carcinoma	0/22
ovary, poorly differentiated carcinoma	5/52
ovary, dysgerminoma	1/121
ovary, yolk sac tumour	1/121
thyroid, hyperplasia	0/12
thyroid, Hashimoto's	0/12
thyroid, adenoma	0/22, 1/2(follicular adenoma)21
thyroid, follicular carcinoma	11/11(weak in all 11 cases)2, 1/121
thyroid, papillary carcinoma	9/92, 2/321
thyroid, medullary carcinoma	0/72
thyroid, anaplastic carcinoma	0/12
adrenal neuroblastoma	1/121
adnexal adenoid cystic carcinoma	1/1(strong)2
malignant melanoma	36/402, 8/21(non-desmoplastic)21, 1/10(desmoplastic)21
skin, Merkel cell carcinoma	3/321
lymphoma	7/492
brain, glioma	5/62
testicular embryonal carcinoma	7/7(moderate in all 7 cases)2
testicular yolk sac tumour	3/3(moderate in all 3 cases)2, 1/221
testicular seminoma	5/52, 18/2121
testis, teratoma	1/221
testis, mixed germ cell tumour	3/621
seminomas/dysgerminomas	23/23(typical cell membrane)17
liposarcoma	0/32
leiomyosarcoma	4/6(weak in 4 cases)2
angiosarcoma	1/1(weak)2
Ewing's sarcoma	0/12
alveolar soft part sarcoma	0/12
clear cell sarcoma	5/10(weak in 5 cases)2
epithelioid sarcoma	5/10(weak in 5 cases)2
rhabdomyosarcoma	3/5(weak in 3 cases)2
synovial sarcoma	7/82
sarcoma NOS	14/23(weak)2
brain, oligodendroglyoma	2/221
brain, medulloblastoma	2/321
brain, ependymoma	1/221
brain, esthesioneuroblastoma	1/121
diffuse large B-cell lymphoma	1/321
Total	305/5762

rarely positive in T-ALL/T-LBL
by malignant phyllodes tumours:

	benign phyllodes tumour	17/101 (17%)15
	borderline phyllodes tumour	12/50 (24%)15
	malignant phyllodes tumour	13/28 (46%)15

CD117 is NOT expressed by:

smooth muscle tumours4
neural tumours4
yolk sac tumours16

Expression of CD117 and CD34 appears to be reduced in chronic intestinal pseudo-obstruction, indicating that this syndrome may be due to loss of the interstitial cells of Cajal and their pacemaker function12.

Diagnostic utility

The diagnostic utility is limited by the wide range of tissues in which CD117 is expressed:

gastrointestinal stromal tumours
mast cell disorders; CD117 should reliably differentiate mast cell tumours from lymphomas. However, AML may stain for CD1178.
germ cell tumours. Staining is membranous in intratubular germ cell neoplasia and seminoma, but cytoplasmic in non-seminomatous germ cell neoplasms8.
The differential diagnosis of eosinophilic renal tumours: granular variant of renal cell carcinoma, chromophobe renal cell carcinoma and oncocytoma.
Assessment of the density of Interstitial Cells of Cajal in slow transit constipation22.

References

1 Bates AW, Feakins RM, Scheimberg I. Congenital gastrointestinal stromal tumour is morphologically indistinguishable from the adult form. but does not express CD117 and carries a favourable prognosis. Histopathology 2000;37:316-322.

2 Arber DA 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;28:498-504.

3 Tsuura Y et al. Preferential localization of c-kit product in tissue mast cells of skin, epithelial cells of breast, small cell lung carcinoma and seminoma/dysgerminoma in human: immunohistochemical study on formalin-fixed, paraffin-embedded tissues. Virchows Archiv A Pathol Anat 1994;424:135-141.

4 JF Graadt van Roggen et al. The histopathological differential diagnosis of gastrointestinal stromal tumours. J Clin Pathol 2001; 54: 96-103.

5 Advances in Anatomic Pathology (news in brief) 2001;8:304.

6 Berman, J., O'Leary, T. J. Gastrointestinal stromal tumor workshop Human Pathol 2001; 32:578-582.

7 Jordan, J. H., Walchshofer, S., Jurecka, W., Mosberger, I., Sperr, W. R., Wolff, K., Chott, A., Buhring, H. J., Lechner, K., Horny, H. P., Valent, P. Immunohistochemical properties of bone marrow mast cells in systemic mastocytosis: evidence for expression of CD2, CD117/Kit, and bcl-x(L) Hum Pathol 2001;32:545-552.

8 Gibson, P. C., Cooper, K. CD117 (KIT): a diverse protein with selective applications in surgical pathology. Adv Anat Pathol 2002;9:65-69.

9 Sabah M, Cummins R, Leader M. Immunohistochemical detection of CD117 expression in soft tissue sarcomas. Pathological Society, July 2002, abstract no 49.

10 JF Graadt van Roggen et al. The histopathological differential of diagnosis of gastrointestinal stromal tumours. J Clin Pathol 2001; 54: 96-102.

11 Leong A S-Y, Cooper K and Leong FJ W-M. Manual of diagnostic antibodies for immunohistology. 2nd edition, 2003

12 Streutker, C.J., Huizinga, J.D., Campbell, F., Ho, J. and Riddell, R.H. Loss of CD117 (c-kit)- and CD34-positive ICC and associated CD34- positive fibroblasts defines a subpopulation of chronic intestinal pseudo-obstruction. Am J Surg Pathol 2003;27:228-35.

13 Miliaras, D., F. Karasavvidou, et al. (2004). "KIT expression in fetal, normal adult, and neoplastic renal tissues." J Clin Pathol 57(5): 463-466.

14 Petit, A., M. Castillo, et al. (2004). "KIT Expression in Chromophobe Renal Cell Carcinoma: Comparative Immunohistochemical Analysis of KIT Expression in Different Renal Cell Neoplasms." Am J Surg Pathol 28(5): 676-678.

15 Tse, G. M., T. C. Putti, et al. (2004). "Increased c-kit (CD117) expression in malignant mammary phyllodes tumors." Mod Pathol 17(7): 827-31.

16 Ramalingam, P., A. Malpica, et al. (2004). "The use of cytokeratin 7 and EMA in differentiating ovarian yolk sac tumors from endometrioid and clear cell carcinomas." Am J Surg Pathol 28(11): 1499-1505.

17 Tian, Q., H. F. Frierson, Jr., et al. (1999). "Activating c-kit gene mutations in human germ cell tumors." Am J Pathol 154(6): 1643-7. FULL TEXT

18 Wang HY,Mills SE. KIT and RCC are useful in distinguishing chromophobe renal cell carcinoma from the granular variant of clear cell renal cell carcinoma. Am J Surg Pathol 2005; 29:640-6

19 Mojica WD, Saxena R, Starostik P, et al. CD117+ small cell lung cancer lacks the asp 816-->val point mutation in exon 17. Histopathology 2005; 47:517-22

20 Makhlouf HR, Remotti HE,Ishak KG. Expression of KIT (CD117) in angiomyolipoma. Am J Surg Pathol 2002; 26:493-7

21 Espinosa I, Lee CH, Kim MK, et al. A novel monoclonal antibody against DOG1 is a sensitive and specific marker for gastrointestinal stromal tumors. Am J Surg Pathol 2008; 32:210-8 Further information available on line