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

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:

 

strong

mast cell disease

11/112, 22/227

breast, invasive ductal carcinoma

19/472, 1/921

breast, lobular carcinoma

0/32

breast, DCIS

2/22

lung, adenocarcinoma

26/342, 1/821

non small cell carcinoma of the lung

8/1443

lung, squamous cell carcinoma

15/212, 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

4/52

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

1/12

liver, hepatocellular carcinoma

2/32

bladder, transitional cell carcinoma

15/242, 1/421, 3/1421

bladder, adenocarcinoma

1/321

prostate, adenocarcinoma

6/292

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

2/22

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, 1/221

thyroid, follicular carcinoma

11/112, 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

1/12

malignant melanoma

36/402, 8/2121, 1/1021

skin, Merkel cell carcinoma

3/321

lymphoma

7/492

brain, glioma

5/62

testicular embryonal carcinoma

7/72

testicular yolk sac tumour

3/32, 1/221

testicular seminoma

5/52, 18/2121

testis, teratoma

1/221

testis, mixed germ cell tumour

3/621

seminomas/dysgerminomas

23/2317

liposarcoma

0/32

leiomyosarcoma

4/62

angiosarcoma

1/12

Ewing's sarcoma

0/12

alveolar soft part sarcoma

0/12

clear cell sarcoma

5/102

epithelioid sarcoma

5/102

rhabdomyosarcoma

3/52

synovial sarcoma

7/82

sarcoma NOS

14/232

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

 

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:

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:

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

22 Wang LM, McNally M, Hyland J, et al. Assessing interstitial cells of Cajal in slow transit constipation using CD117 is a useful diagnostic test. Am J Surg Pathol 2008; 32:980-5

This page last revised 12.7.2008.

©SMUHT/PW Bishop