Carney Triad

The term Carney Triad refers to the occurrence of at least 2 of the following tumor types:

gastrointestinal stromal tumor (GIST)
pulmonary chondroma
extra-adrenal paraganglioma

In a small percentage of affected patients, either of these other tumors may also occur:

adrenocortical adenoma (a benign tumor of the adrenal gland)
esophageal leiomyoma (a benign tumor of the esophagus).

Carney Triad is an extremely rare syndrome, with fewer than 30 cases reported with all three tumors present, and fewer than 100 incomplete cases having two of the three tumor types present. Please refer to the full paper by Carney (1999) from which the following points are summarized. Carney triad predominately affects females (about 85% of cases), with the first tumor appearing before age 20 in about 45% of patients, or between ages 20 and 30 years in another approximately 45% of cases (see Figure 1 of Carney, 1999). At initial diagnosis, only one tumor type is usually present (65% of cases), and this initial tumor is usually gastric GIST.

Because there may be a long time lapse between identification of the first tumor and appearance of the second type of tumor, all pediatric GIST cases should be considered as potential Carney Triad cases, particularly if the patient is female and there are multiple tumors in the stomach.

In the 79 patients summarized by Carney in 1999, 22% eventually developed all three of the tumor types, while 53% showed GIST and chondroma, 24% showed GIST and paraganglioma, and 1% showed chondroma and paraganglioma without GIST. There is often a time lapse of over 5 years before appearance of the second tumor type (median = 6 years and mean = 8.4 years) and some patients have shown an interval of over 20 years before developing a second tumor type.

Carney triad is not a familial disease and is not passed on from generation to generation (Matyakhina et al, 2007).

GIST component

The GISTs in Carney triad usually occur inside the stomach and are usually multi-focal (multiple separate tumors). Occasionally they occur in the portion of the duodenum nearest to the stomach (proximal duodenum). Recent reports indicate that the GISTs of Carney Triad are positive for expression of KIT protein (CD117) by immunohistochemistry (Spatz et al, 2004; Boccon-Gibod et al, 2004; Diment et al, 2005; Horenstein et al, 2005; Delamarre et al, 2006; Knop et al, 2006). Under the microscope, the tumors are made up of cells with different shapes: spindle cells or epithelioid (round) cells or both types of cells. GIST samples from three Carney triad patients have been tested for mutations in the genes for KIT and PDGFRA, but mutation of these genes was not found (Diment et al, 2004; Spatz et al, 2004; Knop et al, 2006). Imatinib (Gleevec) had no apparent benefit for the female patients described by Diment et al (2004) or Spatz et al (2004). However, Delemarre et al (2006) reported a male patient for whom imatinib (Gleevec) was effective in shrinking the size of liver metastases.

The GIST of Carney Triad is less aggressive than typical sporadic GIST and the prognosis is better than in cases of the sporadic GIST that occurs in older adults. Even when the Carney triad GIST does metastasize, patients typically live for many years. Surgical resection (as by partial gastrectomy) is the treatment for GISTs, but independent new GISTs may develop later in the remaining stomach, requiring complete gastrectomy. Post-surgical metastasis of GIST within the abdomen occurred in 55% of patients; sites of metastasis included liver, peritoneum, and gastric lymph nodes. Metastases occurred as long as 33 years after initial surgery. Metastasis to non-abdominal sites was rare (3%). Repeated surgeries may be required to control metastases.

Chondroma component

Pulmonary chondromas are benign cartilaginous lung tumors. They are sometimes known as chondromatous hamartomas. They rarely cause symptoms, but occasionally may result in wheezing or shortness of breath. Carney (1999) reported that chondromas developed in 76% of patients. One case history (Spatz et al, 2004) reported chondromas that were positive for KIT expression. The tumors are cured by surgery, though some small, asymptomatic chondromas may be left untreated since they are benign. Vogl et al (2004) report successful thermal ablation of chondromas.

Paraganglioma component

Carney (1999) found that paragangliomas occurred in 47% of 79 Triad patients. Paragangliomas are rare tumors arising from neural-crest-derived chromaffin cells located in certain areas of the head, neck, chest and abdomen. For summaries about paraganglioma (not specific to Carney Triad) see Young (2006); Pham et al (2006); and Plouin and Gimenez-Roqueplo (2006). The tumors arise from chromaffin cells of the sympathetic nervous system that are located near the spine (vertebral column) from the neck to the pelvis. Chromaffin cells of the parasympathetic nervous system are found in the skull base and neck. Paragangliomas occasionally develop from non-chromaffin paraganglia near the middle ear cavity, sometimes causing ringing in the ears (tinnitus) or hearing loss. If located in the head or neck, paragangliomas may cause “mass effect” symptoms (such as compression of a nerve) that allow their detection. Carney Triad patients may develop multiple independent paragangliomas, which may be either “functioning” or “non-functioning.” “Functioning” paragangliomas produce excess catecholamines, causing symptoms of high blood pressure (hypertension), fast heartbeat, shortness of breath, and headache. These symptoms occur in episodes lasting from a few minutes to several hours. If “functioning” paraganglioma is suspected, blood tests or urine tests can detect excess catecholamines. Imaging tests may then be done to identify the location of the paraganglioma. Surgical resection has been the usual treatment, but it can be complicated because these tumors are highly vascular and may be located next to the aorta and other major blood vessels (Colwell et al, 2001). Recently Vogl et al (2004) reported successful embolization of paragangliomas as a less invasive treatment approach. One case history (Horenstein, 2005) reported paragangliomas that were positive for KIT expression.

Ongoing research

The mutation(s) responsible for Carney Triad have not yet been identified, but this is an area of active investigation by Dr. Carney and his colleagues. A large group of collaborators, including Dr. Carney and Dr. Stratakis (Matyakhina et al, 2007) has performed genetic analyses of GISTs, paragangliomas, and pulmonary chondromas (41 tumors from 37 patients) and found no mutations in the genes for KIT or PDGFRA, consistent with analysis of a handful of prior cases reported above. However, many of the tumors did show loss of genetic material on chromosome 1 in locations which may indicate involvement of succinate dehydrogenase enzymes in the development of Triad.

Amieux (2004) has suggested a possible connection to hypoxia-inducible factor 1-alpha.

The Consortium
for Pediatric and Wildtype GIST Research, a collaborative effort associated with the NIH Pediatric & Wildtype GIST Clinic, is actively pursuing additional research. See the NIH website for details.

Resources

You can read Dr. Carney’s memoir about discovering Carney Triad on our site under Ask the Professional.

References and Additional Bibliography

Papers are arranged alphabetically by name of the first author.
To see the abstract of the paper in PubMed, click the title. Some papers are free-access; for these the link to the full text is included.

Agaimy A, Wuensch PH.
Gastrointestinal stromal tumours in patients with other-type cancer: a mere coincidence or an etiological association? A study of 97 GIST cases.
Z Gastroenterol. 2005 Sep;43(9):1025-30.
PMID: 16142610

Allievi A, Araya V, Calvar C, Cimino C, Delle Piane H, Diaz G, Gianni M, Prudkin L.
[Incomplete Carney’s Triad and arterial hypertension in a young woman]
Medicina (B Aires). 2006;66(1):43-5. Spanish.
PMID: 16555728

Albaroudi S, Ahallat M, Hosni K, Sabbah F, Hrora A, Rais M, Tounsi A.
[Carney’s triad: a new case]
Ann Chir. 2005 Oct;130(9):577-80. Epub 2005 Jul 5. French.
PMID: 16229813

Alberto VO, Kelleher D, Denholm RB, Nutt M, Carney JA.
A calcified lung tumour and microcytic anaemia in a young woman: partial expression of the Carney triad.
Surgeon. 2008 Aug;6(4):249-51.
PMID: 18697369

Amieux PS.
Getting the GIST of the Carney Triad: growth factors, rare tumors, and cellular respiration.
Pediatr Dev Pathol. 2004 Jul-Aug;7(4):306-8. Epub 2004 Jul 15. No abstract available.
PMID: 15383926

Barcena R, Erdozain JC, San Roman AL, Garcia M, Boixeda D, Perez FA.
[Carney’s triad: a short review apropos a case]
Rev Clin Esp. 1992 May;190(8):410-2. Review. Spanish.
PMID: 1620943

Bladen JC, Moosajee M, Bassett JH.
A tense case–Carney’s triad.
J R Soc Med. 2004 Nov;97(11):540-1. No abstract available.
PMID: 15520151

Boccon-Gibod L, Boman F, Boudjemaa S, Fabre M, Leverger G, Carney AJ.
Separate occurrence of extra-adrenal paraganglioma and gastrointestinal stromal tumor in monozygotic twins: probable familial Carney syndrome.
Pediatr Dev Pathol. 2004 Jul-Aug;7(4):380-4. .
PMID: 15383933

Cardwell RJ, Solaiman AR, Kim K, Thomford NR.
Carney’s triad with recurrent gastric leiomyoblastoma.
Am Surg. 1990 Jun;56(6):355-9.
PMID: 2161630

Carney JA.
Gastric stromal sarcoma, pulmonary chondroma, and extra-adrenal paraganglioma (Carney Triad): natural history, adrenocortical component, and possible familial occurrence.
Mayo Clin Proc. 1999 Jun;74(6):543-52.
PMID: 10377927 Full paper available free: link through title.

Carney JA.
The triad of gastric epithelioid leiomyosarcoma, pulmonary chondroma, and functioning extra-adrenal paraganglioma: a five-year review.
Medicine (Baltimore). 1983 May;62(3):159-69.
PMID: 6843355

Carney JA.
The triad of gastric epithelioid leiomyosarcoma, functioning extra-adrenal paraganglioma, and pulmonary chondroma.
Cancer. 1979 Jan;43(1):374-82. Review.
PMID: 367573

Carney JA, Stratakis CA.
Familial paraganglioma and gastric stromal sarcoma: a new syndrome distinct from the Carney triad.
Am J Med Genet. 2002 Mar 1;108(2):132-9.
PMID: 11857563

Carney JA, Sheps SG, Go VL, Gordon H.
The triad of gastric leiomyosarcoma, functioning extra-adrenal paraganglioma and pulmonary chondroma.
N Engl J Med. 1977 Jun 30;296(26):1517-8. No abstract available.
PMID: 865533

Colwell AS, D’Cunha J, Maddaus MA.
Carney’s triad paragangliomas.
J Thorac Cardiovasc Surg. 2001 May;121(5):1011-2. No abstract available.
PMID: 11326257

Cuilleret J, Baril A, Boucheron S, Pichon A, Serpantie P.
[Carney’s triad]
Presse Med. 1984 Jan 21;13(2):79-82. French.
PMID: 6320155

Delemarre L, Aronson D, van Rijn R, Bras H, Arets B, Verschuur A.
Respiratory symptoms in a boy revealing Carney triad.
Pediatr Blood Cancer. 2006 Oct 12; [Epub ahead of print]
PMID: 17039489

Diment J, Tamborini E, Casali P, Gronchi A, Carney JA, Colecchia M.
Carney triad: case report and molecular analysis of gastric tumor.
Hum Pathol. 2005 Jan;36(1):112-6.
PMID: 15712189

Feuls R, Horger M, Erdtmann P.
[Pulmonary chondromas and the Carney triad]
Rofo. 2001 Dec;173(12):M339-40. German. No abstract available.
PMID: 11917854

Jabbour SA, Miller JL.
A case of the Carney triad.
Endocr Pract. 1999 Sep-Oct;5(5):266-8.
PMID: 15251665

Kiryu T, Kawaguchi S, Matsui E, Hoshi H, Kokubo M, Shimokawa K.
Multiple chondromatous hamartomas of the lung: a case report and review of the literature with special reference to Carney syndrome.
Cancer. 1999 Jun 15;85(12):2557-61. Review.
PMID: 10375102

Knop S, Schupp M, Wardelmann E, Stueker D, Horger MS, Kanz L, Einsele H,
Kroeber SM.
A new case of Carney triad: gastrointestinal stromal tumours and leiomyoma of the oesophagus do not show activating mutations of KIT and platelet-derived growth factor receptor alpha.
J Clin Pathol. 2006 Oct;59(10):1097-9.
PMID: 17021135

Lacquet LK, Jongerius CM, Limburg M, Rensing JB.
[The triad: mediastinal chemodectoma, chondroma of the lung and esophageal leiomyoma]
Rev Pneumol Clin. 1984;40(1):63-7. French.
PMID: 6326247

Lancha C, Diez L, Mitjavila M, Rueda M, Crespo A.
A case of complete Carney’s syndrome.
Clin Nucl Med. 1994 Nov;19(11):1008-10.
PMID: 7842572

Lipcan MT 3rd, Loren DE, Palazzo JP, Bibbo M, Dimarino AJ, Cohen S.
Endosonographic diagnosis of recurrent gastrointestinal stromal tumors associated with Carney’s syndrome.
Gastroenterology. 2005 Jan;128(1):169-74.
PMID: 15633134

Matyakhina L, Bei TA, McWhinney SR, Pasini B, Cameron S, Gunawan B, Stergiopoulos SG, Boikos S, Muchow M, Dutra A, Pak E, Campo E, Cid MC, Gomez F, Gaillard RC, Assie G, Fuzesi L, Baysal BE, Eng C, Carney JA, Stratakis CA.
Genetics of Carney triad: recurrent losses at chromosome 1 but lack of germline mutations in genes associated with paragangliomas and gastrointestinal stromal tumors.
J Clin Endocrinol Metab. 2007 May 29; [Epub ahead of print] FREE ACCESS
PMID: 17535989

Miettinen M, Lasota J, Sobin LH.
Gastrointestinal stromal tumors of the stomach in children and young adults: a clinicopathologic, immunohistochemical, and molecular genetic study of 44 cases with long-term follow-up and review of the literature.
Am J Surg Pathol. 2005 Oct;29(10):1373-81.
PMID: 16160481

Mori S, Yoshioka H, Fukui T, Usami N, Uchiyama M, Sato N, Ito M, Kaji M, Ueda Y.
[Carney triad; report of a case]
Kyobu Geka. 2005 Jul;58(7):597-601. Review. Japanese.
PMID: 16004346

Perez-Atayde AR, Shamberger RC, Kozakewich HW.
Neuroectodermal differentiation of the gastrointestinal tumors in the Carney triad. An ultrastructural and immunohistochemical study.
Am J Surg Pathol. 1993 Jul;17(7):706-14.
PMID: 8317611

Pham TH, Moir C, Thompson GB, Zarroug AE, Hamner CE, Farley D, van Heerden J, Lteif AN, Young WF Jr.
Pheochromocytoma and paraganglioma in children: a review of medical and surgical management at a tertiary care center.
Pediatrics. 2006 Sep;118(3):1109-17.
PMID: 16951005

Plouin PF, Gimenez-Roqueplo AP.
Initial work-up and long-term follow-up in patients with phaeochromocytomas and paragangliomas.
Best Pract Res Clin Endocrinol Metab. 2006 Sep;20(3):421-34. Review.
PMID: 16980203

Qiao GB, Zeng WS, Peng LJ, Zhong WZ, Fang Y, Huang WJ, Wu YL.
Multiple pulmonary chondromas in a young female patient: a component of Carney triad.
J Thorac Oncol. 2009 Jun;4(6):751-2. No abstract available.
PMID: 19461402

Raafat F, Salman WD, Roberts K, Ingram L, Rees R, Mann JR.
Carney’s triad: gastric leiomyosarcoma, pulmonary chondroma and extra-adrenal paraganglioma in young females.
Histopathology. 1986 Dec;10(12):1325-33.
PMID: 3028925

Sans N, Durand G, Giron J, Fajadet P, Senac J.
[Carney’s triad: update and report of one case]
J Radiol. 2000 Jan;81(1):39-42. Review. French.
PMID: 10671723

Sawai T, Ikeda T, Ito S, Mochizuki F, Takahashi Y, Rin T, Hayashi T, Kaneko Y, Ohtake H.
[Case of three peculiar tumors of gastric epithelioid leiomyosarcoma, retroperitoneal paraganglioma and pulmonary chondroma]
Gan No Rinsho. 1983 Feb;29(2):A-12, 177-82. Japanese.
PMID: 6876395

Scopsi L, Collini P, Muscolino G.
A new observation of the Carney’s triad with long follow-Up period and additional tumors.
Cancer Detect Prev. 1999;23(5):435-43.
PMID: 10468897

Tzankov A, Schwanninger J, Mikuz G, Mairinger T.
Atypical Carney’s triad with coincidental clear cell renal carcinoma in an 84-year old patient-a finding at autopsy.
Cancer Detect Prev. 2003;27(4):256-8.
PMID: 12893072

Valverde K, Henderson M, Smith CR, Tal
lett S, Chan HS.
Typical and atypical Carney’s triad presenting with malignant hypertension and papilledema.
J Pediatr Hematol Oncol. 2001 Nov;23(8):519-24.
PMID: 11878780

Vogl TJ, Lehnert T, Wetter A, Mack MG, Wurster MG.
Interventional radiology in Carney triad.
Eur Radiol. 2005 Apr;15(4):833-7.
PMID: 15108016

Wahid ST, Jones R, Chawla SL, Connolly VM, Kelly WF, Bilous RW.
A new variant of Carney’s triad: phaeochromocytoma and chondrosarcoma.
Postgrad Med J. 2001 Aug;77(910):527-8. Review.
PMID: 11470935

Wales PW, Drab SA, Kim PC.
An unusual case of complete Carney’s triad in a 14-year-old boy.
J Pediatr Surg. 2002 Aug;37(8):1228-31.
PMID: 12149713

Young WF Jr.
Paragangliomas: clinical overview.
Ann N Y Acad Sci. 2006 Aug;1073:21-9. Review.
PMID: 17102068