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
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ovarian sex cord stromal tumours:
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granulosa cell tumour
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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
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Sertoli-Leydig cell tumours
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12/135, 7/87, 1/19, 10/1118, 7/1121, 8/814, 3/322
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Sertoli cell tumour
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4/45, 17/1712, 6/1121, 1/114
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thecoma
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8/95, 16/1812, 10/1121
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fibrothecoma
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11/145, 4/57, 10/109,
4/6(the two negative cases were predominantly fibromatous)14, 10/1420
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sclerosing stromal tumour
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2/25, 0/212, 2/214, 4/1121
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steroid cell
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3/35, 6/612, 2/214, 8/921
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other stromal neoplasms
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3/35
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primitive gonadal stromal tumour
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5/67, 2/314
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gonadoblastoma
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3/314, 2/521
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gynandroblastoma
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1/114,
1/1(positive in adult and juvenile granulosa cell components)15, 1/121
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sex cord tumour with annular tubules
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2/214,
12/12(10 primary, 2 metastatic)21, 1/122
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lipid cell tumour
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6/77, 1/19
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sex cord stromal tumours, NOS
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17/1820, 1/221
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sex cord-stromal tumours, overall
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80/875,
50/50(37/50 showed moderate to strong staining)8
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other primary ovarian tumours:
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fibroma
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17/205, 0/1212, 3/1121, 2/321
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adenofibroma
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0/95
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fibrosarcoma
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5/85, 0/1021
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serous carcinoma
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1/115, 1/28, 0/726
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atypical mucinous neoplasm / mucinous adenocarcinoma
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0/195, 0/526
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primary ovarian clear cell carcinoma
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0/75, 2/28, 1/116
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endometrioid carcinoma
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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
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sertoliform endometrioid carcinoma
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0/87
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epithelial tumours, NOS
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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
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Brenner tumour
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0/135, 1/920
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Wolffian adnexal tumour
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9/1021
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malignant mixed Müllerian tumour
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0/25, 0/1212
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dysgerminoma
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0/75, 0/618
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yolk sac tumour
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0/55
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choriocarcinoma
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0/15
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embryonal carcinoma
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0/15
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immature teratoma
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0/45
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mixed germ cell tumour
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0/45, 0/612,
1/24(positivity in one case in a focus of syncytiotrophoblast)21
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ovarian small cell carcinoma
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0/15,
0/7(hypercalcaemic type)7, 0/712, 0/1218,
0/12(hypercalcaemic type)21,
0/1(hypercalcaemic type)14
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extrauterine endometrial stromal sarcomas
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0/57, 0/214
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clear cell sarcoma
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0/15
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haemangiopericytoma
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0/15
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myxoma
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0/312
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carcinoid
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0/518,
0/3(staining only of reactive stromal cells)14
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lymphoma
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0/17, 0/212, 0/318, 0/514
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struma ovarii
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0/114
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tumours metastatic to ovary:
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metastatic carcinoma to ovary
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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
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metastatic uterine clear cell carcinoma
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1/38
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metastatic melanoma
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0/17
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metastatic carcinoid to ovary
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0/2(from gastrointestinal tract)14
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endometrial stromal sarcoma metastatic from uterus
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0/214
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testicular tumours:
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Leydig cell tumour
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15/1617
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testicular sex cord-stromal tumors with varying degrees of Sertoli or granulosa cell differentiation
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4/617
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sex cord-stromal tumors, NOS
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2/317
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extra-ovarian tumours:
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uterine endometrioid carcinoma
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1/28,
3/5(weak)26
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thyroid carcinoma
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1/4(strong)26
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colonic adenocarcinoma
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9/12(1 strong, 8 weak)26
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gallbladder adenocarcinoma
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0/526
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pancreatic adenocarcinoma
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0/326
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breast carcinoma
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1/88,
4/9(1 strong, 3 weak)26
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lung adenocarcinoma
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2/5(1 strong, 1 weak)26
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gastric adenocarcinoma
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0/726
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renal cell carcinoma
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1/5(strong)26
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prostatic adenocarcinoma
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0/726
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bladder adenocarcinoma
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0/226
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transitional cell carcinoma
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1/38
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haemangiopericytoma
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0/3(in males)10
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malignant melanoma
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1/58
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extra-ovarian stromal tumours
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granular cell tumour
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19/2028
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gastrointestinal stromal tumours
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0/3227
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leiomyosarcoma
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0/28(20 uterine, 2 colon, 2 skin, 2 retroperitoneal, 1 urinary bladder)27
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endometrial stromal sarcoma
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1/15(weak positivity only in one case in sex-cord like areas)27
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uterine undifferentiated sarcoma
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0/427
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trophoblast
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decidua
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intrauterine products of conception
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36/36(villous trophoblast and extravillous trophoblastic giant cells and some extravillous mononuclear trophoblastic cells)25
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5/40
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extrauterine products of conception
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4/4(villous trophoblast and extravillous trophoblastic giant cells and some extravillous mononuclear trophoblastic cells)25
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1/425
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decidualised endometrium in context of ectopic gestation
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2/725
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decidualised endometrium in context of progesterone therapy
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2/825
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Extrauterine decidualised tissue in context of intrauterine pregnancy
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1/325
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hydatidiform mole
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5/5(villous trophoblast)25
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uterine choriocarcinoma
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2/2(strong staining of scattered cells, both mononuclear and multinucleate)25
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testicular embryonal carcinoma with syncytiotrophoblastic giant cells
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6/6(syncytiotrophoblastic giant cells)25
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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:
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serous adenocarcinoma of ovary
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4/7(weak)26
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mucinous adenocarcinoma of ovary
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2/5(weak)26
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endometrioid adenocarcinoma of ovary
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1/2(weak)26
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endometrial adenocarcinoma
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5/5(weak)26
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colonic adenocarcinoma
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10/12(1 strong, 9 weak)26
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lung adenocarcinoma
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5/5(1 strong, 4 weak)26
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breast carcinoma
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7/9(weak)26
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gastric adenocarcinoma
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2/7(weak)26
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prostatic adenocarcinoma
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3/7(weak)26
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bladder adenocarcinoma
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0/226
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gallbladder adenocarcinoma
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1/5(weak)26
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renal cell carcinoma
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3/5(weak)26
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pancreatic adenocarcinoma
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2/3(weak)26
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thyroid carcinoma
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1/4(weak)26
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Diagnostic utility of a-inhibin
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Identification of ovarian granulosa cell tumours and Sertoli cell tumours:
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Differentiation of sex cord stromal tumours from reactive mesothlium in peritoneal washings, a situation in which calretinin is unhelpful6.
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Possibly in the identification of choriocarcinoma25
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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