Tumors Associated with Carney Complex, Carney Triad and Carney-Stratakis Syndrome

Ricardo V. Lloyd MD, PhD

Adrenal Primary Pigmented Nodular Adrenocortical Disease

Adrenal PPNAD – Cortical Nodules Brown-black nodules 0.1 to 0.5 cm in cortex Nodules usually at cortico-medullary junction Large eosinophilic cells with lipofuscin Myelolipomatous change Carney Complex Pituitary Lesions

• GH Pituitary adenomas

• PRL or mixed GH/PRL adenomas

• GH Pituitary hyperplasia

Carney Complex Cardiac Carney Complex - Lentigenes

Carney Complex Blue nevi (epithelioid)

Pigmented Sertoli cell schwannoma tumor

Carney et al -NEJM 296:1517,1977

• Gastric (epithelioid) leiomyosarcoma

• Funtioning extra-adrenal paraganglioma

• Pulmonary chondroma Carney Triad

• All unrelated young female patients • Two patients had all three tumors • Five other patients with2 of 3 tumors • One patient also with a non-funtioning adrenocortical adenoma • Tumor pattern of multifocal lesions in multiple organs in young patients—suggested an inherited disorder. Carney Triad

• Gastrointestinal stromal tumors

• Paragangliomas

• Pulmonary chondromas

Molecular Abnormalities

• Sporadic GISTs—14q, 22q, 1p

• Carney Triad GISTs—1p loss • (14q, 22q loss uncommon) Familial Paraganglioma and Gastric Stromal Tumors(Carney-Stratakis)

• Twelve patients (7M/5F) • Average age 23 • Autosomal dominant inheritance • 7 Paragangliomas (4 Pg and GIST, 1 GIST) • Paragangliomas multicentric • GIST multifocal

Zhang et al Am J Surg Pathol 34: 53,2010 GISTs in Carney Triad

• Female predilection • Young patient age • Epithelioid cell predominance • Frequent lymph node metastasis • Serial tumor recurrence • Unpredictable behavior

Zhang et al Am J Surg Pathol 34:53,2010

Gill et al AM J Surg Pathol, 2010

• Subtypes of GISTs

Type I—Most GISTs—occurs mainly in adults Spindle cell morphology KIT- or PDGFRA-mutant tumors Type 2—Mainly in children and young adults. Epithelioid morphology Not associated with KIT or PDGFRA mutations-exclusively in stomach Gill et al Am J Surg Pathol 34:636,2010 Gill et al Am J Surg Pathol 34:636, 2010 Gill et al Am J Surg Pathol 34:636, 2010 Gaal et al Modern Pathol 24:147,2011 Gaal et al Modern Pathol 24:147, 2011

Succinate dehydrogenase-deficient GISTs are characterized by IGF1R overexpression Angela Chou1, Jason Chen2, Adele Clarkson2, Jaswinder S Samra3,4, Roderick J Clifton-Bligh4,5, Thomas J Hugh3,4 and Anthony J Gill2,4,6

Chou et al Modern Pathol 22, 2222, 2012 Summary • Carney Complex represent a broad constellation of disorders involving the adrenal cortex, heart and many other organs • Carney Triad (CT) includes GISTs, Paragangliomas and Pulmonary Chondromas • Carney –Stratakis Dyad (C-S D) includes GISTs and Paragangliomas • Some GISTs associated with CT and C-S D involve mutations of mitochondrial SDH genes References

• Carney JA, Gordon H, Carpenter PC, Shenoy BV, Go VL. The complex of myxomas, spotty pigmentation, and endocrine overactivity. Medicine (Baltimore) 64: 270-83, 1985. • Carney JA, Stratakis CA. Familial paraganglioma and gastric stromal sarcoma: a new syndrome distinct from the Carney triad. Am J Med Genet 108: 132-9, 2002. • Zhang L, Smyrk TC, Young WF Jr, Stratakis CA, Carney JA. Gastric stromal tumors in Carney triad are different clinically, pathologically, and behaviorally from sporadic gastric gastrointestinal stromal tumors: findings in 104 cases. Am J Surg Pathol 34: 53-64, 2010. • Gaal J, Stratakis CA, Carney JA, Ball ER, Korpershoek E, Lodish MB, Levy I, Xekouki P, van Nederveen FH, den Bakker MA, O’Sullivan M, Dinjens WN, de Krijger RR. SDHB immunohistochemistry: a useful tool in the diagnosis of Carney-Stratakis and Carney triad gastrointestinal stromal tumors. Mod Pathol 24: 147-51, 2011.