Inhibin

Inhibin is a disulphide-linked dimeric 32 kDa glycoprotein hormone composed of a and b subunits. The b subunit exists as at least four isoforms. Inhibin suppresses FSH secretion. Activin, which stimulates FSH secretion, is composed of two b subunits. It is therefore the presence of the a subunit which is specific for inhibin⁶.

Monoclonal antibodies appear to have an narrower range of immunoreactivity than polyclonal antibodies. Most published data is based on the monoclonal R1 antibody from Serotec, which is directed against the a subunit. E4 is directed against the bA subunit and therefore is immunoreactive with both activin and inhibin. Antibodies are effective on paraffin-embedded tissue⁶.

Immunohistochemical expression of a-inhibin

• Normal tissues⁶:

  • ovarian granulosa cells
    
  • theca interna and limited staining of theca externa
    
  • corpora lutea (3/3⁷) and luteomas of pregnancy (7/7⁷, 2/2²¹)
    
  • testicular Sertoli and Leydig cells
    
  • breast tissue
    
  • placental trophoblast
    
  • Endometrium, myometrium and Fallopian tube are reportedly not immunoreactive.
    
  • non-reproductive organs including brain, pituitary, lung, spleen, pancreas, kidney, adrenal and prostate are all reported as immunoreactive. Liver and bone marrow are reportedly not immunoreactive.

• stromal hyperthecosis (8/8¹⁴)

• ovarian sex cord stromal neoplasms. Inhibin is more specific but less sensitive than calretinin.

ovarian sex cord stromal tumours:
granulosa cell tumour	37/39 (30 primary adult, 5 metastatic adult, 3 primary juvenile, 1 metastatic juvenile type)5, 42/43 (31/32 adult primary, 4/4 metastatic, 7/7 juvenile)7, 16/16 (13/13 adult and 3/3 juvenile)9, 6/6 (ovarian primaries)10, 3/3 (metastases, 2 in the liver)10, 6/611, 66/6612 , 5/6 (unilocular cystic granulosa cell tumours)13, 26/26 (24/24 adult, 2/2 juvenile)14, 16/1616, 32/3318, 1/1 (metastatic to CNS)19, 33/3520, 28/28 (14/14 primary adult, 3/3 metastatic adult, 10/10 juvenile primary, 1/1 metastatic juvenile)21, 14/1422
Sertoli-Leydig cell tumours	12/135, 7/87, 1/19, 10/1118, 7/1121, 8/814, 3/322
Sertoli cell tumour	4/45, 17/1712, 6/1121, 1/114
thecoma	8/95, 16/1812, 10/1121
fibrothecoma	11/145, 4/57, 10/109, 4/6 (the two negative cases were predominantly fibromatous)14, 10/1420
sclerosing stromal tumour	2/25, 0/212, 2/214, 4/1121
steroid cell	3/35, 6/612, 2/214, 8/921
other stromal neoplasms	3/35
primitive gonadal stromal tumour	5/67, 2/314
gonadoblastoma	3/314, 2/521
gynandroblastoma	1/114, 1/1 (positive in adult and juvenile granulosa cell components)15, 1/121
sex cord tumour with annular tubules	2/214, 12/12 (10 primary, 2 metastatic)21, 1/122
lipid cell tumour	6/77, 1/19
sex cord stromal tumours, NOS	17/1820, 1/221
sex cord-stromal tumours, overall	80/875, 50/50 (37/50 showed moderate to strong staining)8
other primary ovarian tumours:
fibroma	17/205, 0/1212, 3/1121, 2/321
adenofibroma	0/95
fibrosarcoma	5/85, 0/1021
serous carcinoma	1/115, 1/28, 0/726
atypical mucinous neoplasm / mucinous adenocarcinoma	0/195, 0/526
primary ovarian clear cell carcinoma	0/75, 2/28, 1/116
endometrioid carcinoma	0/155, 2/1220, 0/9 (staining only of reactive stromal cells)14, 0/11 (included six cases simulating sex cord stromal tumours)22, 0/723, 0/12 (ovarian endometrioid carcinomas with sertoliform features: luteinised stromal cells positive in 10 cases)24, 0/226
sertoliform endometrioid carcinoma	0/87
epithelial tumours, NOS	0/19 (the epithelial component is negative; there may be positivity in luteinised stromal cells)7, 0/2212, 4/5118, 3/17 (poorly differentiated primary and metastatic)20, 0/1721, 0/7 (poorly differentiated primary tumours: staining only of reactive stromal cells)14
Brenner tumour	0/135, 1/920
Wolffian adnexal tumour	9/1021
malignant mixed Müllerian tumour	0/25, 0/1212
dysgerminoma	0/75, 0/618
yolk sac tumour	0/55
choriocarcinoma	0/15
embryonal carcinoma	0/15
immature teratoma	0/45
mixed germ cell tumour	0/45, 0/612, 1/24 (positivity in one case in a focus of syncytiotrophoblast)21
ovarian small cell carcinoma	0/15, 0/7 (hypercalcaemic type)7, 0/712, 0/1218, 0/12 (hypercalcaemic type)21, 0/1 (hypercalcaemic type)14
extrauterine endometrial stromal sarcomas	0/57, 0/214
clear cell sarcoma	0/15
haemangiopericytoma	0/15
myxoma	0/312
carcinoid	0/518, 0/3 (staining only of reactive stromal cells)14
lymphoma	0/17, 0/212, 0/318, 0/514
struma ovarii	0/114
tumours metastatic to ovary:
metastatic carcinoma to ovary	0/15 (GI x 5, breast x 2, lung x 1, unknown x7, including two of Krukenberg type: staining only of reactive stromal cells)14
metastatic uterine clear cell carcinoma	1/38
metastatic melanoma	0/17
metastatic carcinoid to ovary	0/2 (from gastrointestinal tract)14
endometrial stromal sarcoma metastatic from uterus	0/214
testicular tumours:
Leydig cell tumour	15/1617
testicular sex cord-stromal tumors with varying degrees of Sertoli or granulosa cell differentiation	4/617
sex cord-stromal tumors, NOS	2/317
extra-ovarian tumours:
uterine endometrioid carcinoma	1/28, 3/5 (weak)26
thyroid carcinoma	1/4 (strong)26
colonic adenocarcinoma	9/12 (1 strong, 8 weak)26
gallbladder adenocarcinoma	0/526
pancreatic adenocarcinoma	0/326
breast carcinoma	1/88, 4/9 (1 strong, 3 weak)26
lung adenocarcinoma	2/5 (1 strong, 1 weak)26
gastric adenocarcinoma	0/726
renal cell carcinoma	1/5 (strong)26
prostatic adenocarcinoma	0/726
bladder adenocarcinoma	0/226
transitional cell carcinoma	1/38
haemangiopericytoma	0/3 (in males)10
malignant melanoma	1/58
extra-ovarian stromal tumours
granular cell tumour	19/2028
gastrointestinal stromal tumours	0/3227
leiomyosarcoma	0/28 (20 uterine, 2 colon, 2 skin, 2 retroperitoneal, 1 urinary bladder)27
endometrial stromal sarcoma	1/15 (weak positivity only in one case in sex-cord like areas)27
uterine undifferentiated sarcoma	0/427

• Uterine tumours with sex cord differentiation(1/2³, 3/7⁴).

• Testicular Leydig cell tumours and Sertoli cell tumours.

• Trophoblast and decidua:

	trophoblast	decidua
intrauterine products of conception	36/36 (villous trophoblast and extravillous trophoblastic giant cells and some extravillous mononuclear trophoblastic cells)25	5/40
extrauterine products of conception	4/4 (villous trophoblast and extravillous trophoblastic giant cells and some extravillous mononuclear trophoblastic cells)25	1/425
decidualised endometrium in context of ectopic gestation		2/725
decidualised endometrium in context of progesterone therapy		2/825
Extrauterine decidualised tissue in context of intrauterine pregnancy		1/325
hydatidiform mole	5/5 (villous trophoblast)25
uterine choriocarcinoma	2/2 (strong staining of scattered cells, both mononuclear and multinucleate)25
testicular embryonal carcinoma with syncytiotrophoblastic giant cells	6/6 (syncytiotrophoblastic giant cells)25

• Inhibin immunoreactivity has been reported in hepatocellular carcinoma and as possibly useful in the differentiation of hepatocellular carcinomas (positive) from adenocarcinomas (negative)¹. However, a subsequent publication indicates that the reported immunopositivity of HCC and non-tumoral hepatocytes for inhibin represents a false-positive result due to endogenous biotin².

Immunohistochemical expression of b-inhibin (activin)

Activin is expressed by ovarian epithelial tumours and is demonstrated by antibody E4. Relatively little has been published, but it does not appear to be specific for ovarian carcinomas²⁶:

serous adenocarcinoma of ovary	4/7 (weak)26
mucinous adenocarcinoma of ovary	2/5 (weak)26
endometrioid adenocarcinoma of ovary	1/2 (weak)26
endometrial adenocarcinoma	5/5 (weak)26
colonic adenocarcinoma	10/12 (1 strong, 9 weak)26
lung adenocarcinoma	5/5 (1 strong, 4 weak)26
breast carcinoma	7/9 (weak)26
gastric adenocarcinoma	2/7 (weak)26
prostatic adenocarcinoma	3/7 (weak)26
bladder adenocarcinoma	0/226
gallbladder adenocarcinoma	1/5 (weak)26
renal cell carcinoma	3/5 (weak)26
pancreatic adenocarcinoma	2/3 (weak)26
thyroid carcinoma	1/4 (weak)26

Diagnostic utility of a-inhibin

• Identification of ovarian granulosa cell tumours and Sertoli cell tumours:

  • differentiation from carcinomas (especially endometrioid carcinoma with a sex cord-like pattern)

  • differentiation of sarcomatoid growth pattern from soft tissue tumours

  • in combination with CD10, the differentiation from ovarian endometrial stromal tumour.

• Differentiation of sex cord stromal tumours from reactive mesothlium in peritoneal washings, a situation in which calretinin is unhelpful⁶.

• Possibly in the identification of choriocarcinoma²⁵

• Possibly in the identification of syncytiotrophoblast in testicular tumours²⁵

References

¹McCluggage WG. Maxwell P. Patterson A. Sloan JM. Immunohistochemical staining of hepatocellular carcinoma with monoclonal antibody against inhibin. Histopathology 1997;30(6):518-22.

²Iezzoni JC. Mills SE. Pelkey TJ. Stoler MH. Inhibin is not an immunohistochemical marker for hepatocellular carcinoma. An example of the potential pitfall in diagnostic immunohistochemistry caused by endogenous biotin.Am J Clin Pathol 1999;111(2):229-34.

³McCluggage, W. G. Uterine tumours resembling ovarian sex cord tumours: immunohistochemical evidence for true sex cord differentiation. Histopathology 1999;34:375-6.

⁴Krishnamurthy, S., Jungbluth, A. A., Busam, K. J., Rosai, J. Uterine tumors resembling ovarian sex-cord tumors have an immunophenotype consistent with true sex-cord differentiation. Am J Surg Pathol 1998;22:1078-1082.

⁵Movahedi-Lankarani, S. and Kurman, R.J. Calretinin, a more sensitive but less specific marker than alpha- inhibin for ovarian sex cord-stromal neoplasms: an immunohistochemical study of 215 cases. Am J Surg Pathol 2002;26:1477-83.

⁶Zheng, W., Senturk, B.Z. and Parkash, V. Inhibin immunohistochemical staining: a practical approach for the surgical pathologist in the diagnoses of ovarian sex cord-stromal tumors. Adv Anat Pathol 2003;10:27-38.

⁷Rishi, M., Howard, L.N., Bratthauer, G.L. and Tavassoli, F.A. Use of monoclonal antibody against human inhibin as a marker for sex cord-stromal tumors of the ovary. Am J Surg Pathol 1997;21:583-9.

⁸Pelkey, T.J., Frierson, H.F., Jr., Mills, S.E. and Stoler, M.H. The diagnostic utility of inhibin staining in ovarian neoplasms. Int J Gynecol Pathol 1998;17:97-105.

⁹Flemming, P., Grothe, W., Maschek, H., Petry, K.U., Wellmann, A. and Georgii, A. The site of inhibin production in ovarian neoplasms. Histopathology 1996;29:465-8.

¹⁰Flemming, P., Wellmann, A., Maschek, H., Lang, H. and Georgii, A. Monoclonal antibodies against inhibin represent key markers of adult granulosa cell tumors of the ovary even in their metastases. A report of three cases with late metastasis, being previously misinterpreted as hemangiopericytoma. Am J Surg Pathol 1995;19:927-33.

¹¹Arora, D.S., Cooke, I.E., Ganesan, T.S., Ramsdale, J., Manek, S., Charnock, F.M., Groome, N.P. and Wells, M. Immunohistochemical expression of inhibin/activin subunits in epithelial and granulosa cell tumours of the ovary. J Pathol 1997;181:413-8.

¹²Costa, M.J., Ames, P.F., Walls, J. and Roth, L.M. Inhibin immunohistochemistry applied to ovarian neoplasms: a novel, effective, diagnostic tool. Hum Pathol 1997;28:1247-54.

¹³Mulvany, N.J. and Riley, C.B. Granulosa cell tumors of unilocular cystic type. Pathology 1997;29:348-53.

¹⁴Stewart, C.J., Jeffers, M.D. and Kennedy, A. Diagnostic value of inhibin immunoreactivity in ovarian gonadal stromal tumours and their histological mimics. Histopathology 1997;31:67-74.

¹⁵McCluggage, W.G., Sloan, J.M., Murnaghan, M. and White, R. Gynandroblastoma of ovary with juvenile granulosa cell component and heterologous intestinal type glands. Histopathology 1996;29:253-7.

¹⁶McCluggage, W.G., Maxwell, P. and Sloan, J.M. Immunohistochemical staining of ovarian granulosa cell tumors with monoclonal antibody against inhibin. Hum Pathol 1997;28:1034-8.

¹⁷McCluggage, W.G., Shanks, J.H., Whiteside, C., Maxwell, P., Banerjee, S.S. and Biggart, J.D. Immunohistochemical study of testicular sex cord-stromal tumors, including staining with anti-inhibin antibody. Am J Surg Pathol 1998;22:615-9.

¹⁸Riopel, M.A., Perlman, E.J., Seidman, J.D., Kurman, R.J. and Sherman, M.E. Inhibin and epithelial membrane antigen immunohistochemistry assist in the diagnosis of sex cord-stromal tumors and provide clues to the histogenesis of hypercalcemic small cell carcinomas. Int J Gynecol Pathol 1998;17:46-53.

¹⁹Schnittger, C., Soudah, B., von Wasielewski, R., de Groot, M., Haubitz, B., Becker, H. and Dengler, R. Infiltration of the central nervous system by a granulosa cell tumor immunostained by antibodies against inhibin. Neurology 1998;50:560-2.

²⁰Hildebrandt, R.H., Rouse, R.V. and Longacre, T.A. Value of inhibin in the identification of granulosa cell tumors of the ovary. Hum Pathol 1997;28:1387-95.

²¹Kommoss, F., Oliva, E., Bhan, A.K., Young, R.H. and Scully, R.E. Inhibin expression in ovarian tumors and tumor-like lesions: an immunohistochemical study. Mod Pathol 1998;11:656-64.

²²Guerrieri, C., Franlund, B., Malmstrom, H. and Boeryd, B. Ovarian endometrioid carcinomas simulating sex cord-stromal tumors: a study using inhibin and cytokeratin 7. Int J Gynecol Pathol 1998;17:266-71.

²³Matias-Guiu, X., Pons, C. and Prat, J. Mullerian inhibiting substance, alpha-inhibin, and CD99 expression in sex cord-stromal tumors and endometrioid ovarian carcinomas resembling sex cord-stromal tumors. Hum Pathol 1998;29:840-5.

²⁴Ordi, J., Schammel, D.P., Rasekh, L. and Tavassoli, F.A. Sertoliform endometrioid carcinomas of the ovary: a clinicopathologic and immunohistochemical study of 13 cases. Mod Pathol 1999;12:933-40.

²⁵McCluggage, W.G., Ashe, P., McBride, H., Maxwell, P. and Sloan, J.M. Localization of the cellular expression of inhibin in trophoblastic tissue. Histopathology 1998;32:252-6.

²⁶McCluggage, W.G. and Maxwell, P. Adenocarcinomas of various sites may exhibit immunoreactivity with anti- inhibin antibodies. Histopathology 1999;35:216-20.

²⁷Shah, V.I., Freites, O.N., Maxwell, P. and McCluggage, W.G. Inhibin is more specific than calretinin as an immunohistochemical marker for differentiating sarcomatoid granulosa cell tumour of the ovary from other spindle cell neoplasms. J Clin Pathol 2003;56:221-4.

²⁸Zamecnik, M., Michal, M. and Mukensnabl, P. Reactivity of granular cell tumors for inhibin and other markers of sex cord and steroid cell differentiation. Am J Surg Pathol 2003;27:413-4.

This page last revised 20.3.2003.

©SMUHT/PW Bishop