Adrenal Cortical Carcinomas with Myxoid Differentiation in Ferrets M. Kiupel,, R.A. Peterson II, C.C. Capen,, D.B. Wilson 4125 Beaumont Road Lansing, MI 48910 www.animalhealth.msu.edu
Signalment 5-year-old female ferret removed adrenal tumor (02/01 bilateral hair loss) development of secondary tumor widespread metastasis necropsy on 11/27/01 clinical history: wasting away 4125 Beaumont Road Lansing, MI 48910 www.animalhealth.msu.edu
Gross Lesions slightly dehydrated, very thin (500 g) abdomen: - 10 ml clotted blood - multiple large masses right adrenal gland (5 cm in diameter): - homogeneous, soft, pink, central cavitation - invaded into abdominal artery - rotated 360 degrees clockwise - rupture of adrenal artery - exsanguination into the abdominal cavity necrohemorrhagic mass: severe fat necrosis large white, firm, nodular mass in the liver 4125 Beaumont Road Lansing, MI 48910 www.animalhealth.msu.edu
Morphological Diagnosis Adrenal Cortical Carcinomas with Myxoid Differentiation 4125 Beaumont Road Lansing, MI 48910 www.animalhealth.msu.edu
Histochemistry myxoid component: negative with Churukian-Schenck argentaffin stain (neuroendocrine( cells) mucinous matrix: positive with Alcin blue ph 2.5 4125 Beaumont Road Lansing, MI 48910 www.animalhealth.msu.edu
Alcian Blue
Immunohistochemistry myxoid component: positive: vimentin,, a-inhibina variably positive: synaptophysin negative: pancytokeratin, CgA,, AFP, SMA increased PCNA LI spindle cell component: positive: SMA 4125 Beaumont Road Lansing, MI 48910 www.animalhealth.msu.edu
Vimentin
Inhibin
PCNA
Retrospective Study 15 ferrets (2 without history) age: 5.38 +/- 1.5 years (3-9 9 years) 6 male castrated, 7 spayed female neutered > 6 months of age clinical signs: hyperestrogenism/space occupying mass polyuria/polydypsia (3/13) symmetric alopecia (13/13) enlarged vulva (3/7), mammary gland (1/7) abdominal distention (4/13) stranguria (3/6), tenesmus (1/13) 4125 Beaumont Road Lansing, MI 48910 www.animalhealth.msu.edu
Adrenal Tumors 0.75-5.50 cm in diameter no predilection for right or left adrenal bilateral tumors (2/13) hepatic metastasis (4/13): 1.0-5.0 cm metastasis to lung, lymph nodes (1/13) myxoid differentiation more prominent in metastatic cases metastatic masses were myxoid 4125 Beaumont Road Lansing, MI 48910 www.animalhealth.msu.edu
Conclusions origin of myxoid cells: unknown most likely adrenal cortex, zona reticularis differentiation into mucin producing cells degeneration of neoplastic cells, stroma? ectopic rests of gonadal stromal granulosa or Sertoli cells?! -negative AFP effects: feminization, hyperestrogenism more malignant than simple ACC similar variant in humans 4125 Beaumont Road Lansing, MI 48910 www.animalhealth.msu.edu
Effect of GDX on HPA axis 4125 Beaumont Road Lansing, MI 48910 www.animalhealth.msu.edu
Transcription factors implicated in gonadal steroidogenesis P450c17
GATA-4
Cyt-b5
LH receptor
Aromatase
P450 c17
Cyt b5 enhances the 17,20-lyase activity of P450c17 through allosteric effects
Conclusions Adrenal glands of healthy ferrets produce only limited amounts of androgenic steroids Adrenocortical neoplasms that arise in neutered ferrets typically secrete androgens or their derivative, estrogen The 17,20-lyase activity of cytochrome P450 17α- hydroxylase/17,20-lyase lyase (P450c17) must increase to permit androgen biosynthesis in neoplastic adrenal tissue Cytochrome-b5 5 (cyt-b5 b5), an allosteric regulator that selectively enhances the 17,20-lyase activity of P450c17, is a novel marker of gonadal-like like differentiation in ferret adrenocortical neoplasms Other sex steroidogenic markers, such as luteinizing hormone receptor, aromatase,, and GATA4, are co-expressed with cyt-b5
References 1. Bielinska M, Kiiveri S, Parviainen H, Mannisto S, Heikinheimo M, Wilson DB. Gonadectomy-induced adrenocortical neoplasia in the domestic ferret (Mustela putorius furo) ) and laboratory mouse. Vet Pathol 43:97 117, 2006. 2. Gliatto JM et al. A light microscopical, ultrastructural and immunohistochemical study of spindle-cell adrenocortical tumors of ferrets. J Comp Pathol 113: 175-183, 183, 1995 3. Peterson RA, Kiupel M, Capen CC Adrenal Cortical Carcinomas with Myxoid Differentiation in the Domestic Ferret (Mustela( putorius furo). Vet Pathol 40: 136-142, 142, 2003. 4. Peterson RA, Kiupel M, Bielinska M, Capen CC Wilson DB. Transcription Factor GATA-4 4 is a Marker of Anaplasia in Adrenocortical Neoplasms of the Domestic Ferret (Mustela( putorius furo) ) Vet pathol 41: 446-449, 449, 2004. 5. Wagner S, Kiupel M, Peterson RA, Heikinheimo M, Wilson DB. Cytochrome b5 Expression in Gonadectomy-induced Adrenocortical Neoplasms of the Domestic Ferret (Mustela( putorius furo). Vet Pathol 45: 439-442, 442, 2008. 6. Rosenthal KL: Hyperadrenocorticism associated with adrenocortical tumor or nodular hyperplasia in ferrets: 50 cases (1987-1991). 1991). JAVMA 203:271-275, 275, 1993. 4125 Beaumont Road Lansing, MI 48910 www.animalhealth.msu.edu