Dr. CarneyGSI asked Dr. Aidan Carney to describe how he came to identify the syndrome of tumors now known as Carney triad, which affects young patients. Dr. Carney, a pathologist, now retired but continuing his research activities, is an emeritus member of the Department of Laboratory Medicine and Pathology at the Mayo Clinic in Rochester, Minnesota. His special interests during his career have included endocrine and gastrointestinal pathology, with a particular interest in syndromes.

The Story of Discovery
of the Carney Triad

by J. Aidan Carney, M.D., Ph.D., F.R.C.P.I., F.R.C.P.

Sometimes it is strange how events turn out. Dr. E.G. Harrison, a colleague in pathology at Mayo Clinic, died unexpectedly on July 4th 1974. One of his interests was a tumor called paraganglioma. Paragangliomas arise from little groups of cells (minute organs) located in certain areas of the body, the adrenal gland, and the carotid and vagal bodies in the neck, for example. They are usually benign. Sometimes, they secrete a chemical (adrenaline) that causes high blood pressure.

In November, 1975 Dr. ER, a pathologist in Iowa, not knowing of Dr. Harrison’s passing, sent him histologic slides because of his special interest in paraganglioma. The slides were from a 25-year-old woman, Ms. AB, who, without warning, vomited a large amount of blood (massive hematemesis) and fainted. She was taken to the local hospital where emergency surgery (a partial gastrectomy) was performed to control the gastric hemorrhage. Dr. ER, on examining the stomach specimen in the laboratory, found 5 tumors, several of which were ulcerated, the cause of the patient’s gastric hemorrhage. The microscopic examination of the tumor cells revealed unusual patterns, including their arrangement in clusters. The patient’s history revealed that fourteen years previously, at age 11, she had a tumor excised from her neck — a paraganglioma of the carotid body. Because of the microscopic similarity between the carotid body paraganglioma and the gastric tumors, Dr. ER tentatively concluded that the stomach tumors were the result of metastases from the carotid body paraganglioma that had been carried by the blood stream from the neck to the stomach. Wishing for a second opinion, she sent the histological slides of the stomach tumors to Dr. Harrison.

Because I had taken up Dr. Harrison’s interest in paragangliomas, the slides were referred to me. And so began my involvement with a previously unrecognized disorder that was later titled the Carney triad. When I examined the slides in the microscope, I could see the reason for Dr. ER’s diagnosis — the microscopic clustering pattern of the gastric tumor cells mimicked the pattern of paraganglioma. However, the sequence of events, as related by Dr. ER, namely, the occurrence of a carotid body paraganglioma in an 11-year-old girl (an age at which tumors are unlikely), followed by the apparent development of gastric metastases (an organ very rarely the seat of metastasis), after a very long interval (14 years is an unusually long time for metastases to develop), seemed improbable. I thought it more likely that carotid body tumor (paraganglioma) and gastric tumors (which I interpreted as epithelioid leiomyosarcomas — the term in use in 1975 for tumors now referred to as GISTs) were different although their microscopic appearances overlapped.

Further, because of the unlikely occurrence of two different and unusual tumors in a young patient (not the time of life when tumors are ordinarily found), and in whom one of the tumors was multiple (the gastric tumor), I thought that the tumors might be have a connection, one to the other. But this was just a guess, based on findings in one case. To prove a relationship, it would be necessary to identify additional similar cases.

I gave Dr. ER my opinion that the gastric tumors were epithelioid leiomyosarcomas and not metastatic paraganglioma. She then told me that she had learned something new about the patient — that she had five pulmonary tumors, three in one lung and two in the other! I was taken aback by this news —now this young patient had tumors in 3 organs. In an effort to explain the new finding, I suggested that the pulmonary tumors were probably spread (metastases) of the gastric tumors to the lung. I discussed the case with a colleague, Dr. Dave Ahmann, an oncologist, who suggested that the pulmonary nodules should be biopsied to confirm that they were metastases before starting chemotherapy.

The findings in the case had raised the intriguing question in my mind — could there possibly be a connection between paraganglioma and gastric epithelioid leiomyosarcoma (GIST)? I thought it worthwhile getting an answer to this — but it would mean going through all Mayo Clinic records of patients with paraganglioma and all patients with gastric epithelioid leiomyosarcomas (which, before computerization, would have been a very time-consuming task) to identify other, if any, patients with both tumors. Since I was working on another project at the time, I could not take up the search immediately. But fortune smiled on me. Shortly afterwards, I met Dr. Sheldon Sheps, the Mayo Clinic expert on paraganglioma. I mentioned Ms. AB’s case to him and my feeling that there might be possibly a connection between the patient’s 2 tumors, the carotid body paraganglioma and the GISTs. Had he come across any such case? He couldn’t recall one but he sent me his list of Mayo Clinic patients who had paraganglioma and another different tumor. The list included 12 patients. Three of them, young women, had gastric GISTs in addition to paraganglioma! When I checked their records, I found that 2 of the 3 also had benign lung cartilaginous tumors!

Immediately, I realized 2 things: first, that there almost certainly existed a previously unrecognized disorder (syndrome) that included paraganglioma and gastric GIST and, second, that the syndrome likely included cartilaginous tumors of the lung also. Straightaway, I called Dr. ER to tell her this and my strong suspicion that Ms. AB’s lung masses were benign cartilaginous tumors. Her response was “You are absolutely right. Last week we removed them, and they were benign hamartomas” (cartilaginous tumors). This clinched the case for me. I was satisfied that I had identified a new and rare disorder that in time was titled in the literature the Carney triad.

The story is not quite finished. Once I concluded that this triad of tumors existed, my experience told me that the disorder should be a familial condition because of the occurrence of multiple tumors in multiple organs in young patients — the pattern of familial tumor syndromes. Dr. Hymie Gordon, a colleague and geneticist, agreed with this assessment of the evidence from the 4 cases. Because we considered it important to study this probability, it was arranged that Ms. AB attend Mayo Clinic in Rochester to investigate this. It turned out that she had no affected family members. Eventually our suspicion that the triad might be familial proved not to be true. None of the more than 100 patients with the Carney triad that I now know of has had an affected family member. The triad is special in this regard — it should be familial but it is not.

I had become very absorbed with Ms. AB’s case, so much so that I wanted to meet her. I didn’t know how to say this to Dr. Gordon because ordinarily pathologists work in a laboratory and do not have occasion to meet patients. As we discussed the arrangements for the appointment, he quite unexpectedly said “And of course, you will want to meet her.” Some days later I had the pleasure and privilege of visiting with Ms. AB. We kept in touch and thereafter I called her every year just before Christmas to see that
all was going well. One year I was in Europe over the Christmas holiday and didn’t call until I got back in the New Year. When I did, she immediately said words to the effect of “You’re late!” Now my wife and I meet each year for dinner with her and her husband when she comes back for a check-up. This year it will be their turn to treat!

If you would like to read more about Carney triad, our GIST Bibliography page includes a link for a PubMed search on the topic. Note that Dr. Carney’s name has also been attached to a different and unrelated disorder known as Carney complex or ‘complex of spotty skin pigmentation, myxomas, endocrine overactivity and schwannomas.’ Therefore, if you search PubMed, do not confuse the two similarly named syndromes.

The following quote is from the concluding paragraph of an editorial summary about Dr. Carney and his dedicated quest to understand the triad by fellow pathologist Henry D. Appelman, M.D. (Mayo Clinic Proceedings, 1999, 74:638-639). “Aidan Carney, with intelligence and perseverance, recognized that not all gastrointestinal stromal tumors are the same and that there is more to them than simply determining the cell types within them or finding features that distinguish the benign ones from the malignant. He observed that a small group of them occurred in a specific clinical setting and that they had a peculiar clinical behavior. He scoured the literature for similar cases and tracked down the authors of most such reports with almost religious fervor to see if those cases were like his. The Aidan Carneys of this world are insightful and creative, and they force those of us who are neither to keep our eyes open, observe things carefully, and question dogma frequently. The Carney triad is not so much a medical issue as it is a medical lesson.”

By special permission of Dr. Carney, Dr. Appleman, and the Mayo Clinic Proceedings, the following two papers about Carney Triad are available on the GIST Support International website:

J. Aidan Carney (1999). Gastric stromal sarcoma, pulmonary chondroma, and extra-adrenal paraganglioma (Carney Triad): natural history, adrenocortical component, and possible familial occurrence. Mayo Clinic Proceedings 74(6): 543-552.

Henry D. Appleman (1999). The Carney Triad: a lesson in observation, creativity, and perseverance. Mayo Clinic Proceedings 74(6): 638-640.