Kaposi's sarcoma (KS) is the most common malignancy in AIDS patients. But before HIV got into the act a quarter-century ago, KS was a benign skin cancer, scarcely more serious than a sunburn.
KS owes its eponymic name to an Austrian dermatologist named Moritz Kaposi (1837-1902). His patients at that time were mostly elderly Jewish and Italian subjects, who had to put up with slow-growing purplish blemishes on hands, feet and buttocks. That was then.
Now, besides chipping in to the morbidity and mortality of AIDS, KS plays a hidden hand in organ transplantation, especially of donor kidneys.
"Tumor cells concealed in a transplanted organ," observed hematologist Mario Luppi, at the University of Modena in Italy, "can cause Kaposi's sarcoma thanks to its infective herpes simplex virus [HSV] - among the most frequent transplant-related malignancies - in the organ recipient. The May issue of Nature Medicine, released online April 7, 2003, carries an article titled "Post-transplant Kaposi sarcoma originates from the seeding of donor-derived progenitors." Luppi is its co-lead author.
"Our general finding in that journal paper," Luppi told BioWorld Today, "is that we demonstrate for the first time that not only is the human herpes virus transmitted from the donor to the recipient, but also infected cells coming from the donor may be seeded through organ transplants, which reinforces that notion. And second, the tumor progenitors themselves may be seeded with an organ, which is a quite unexpected finding. The novel thing is the fact that, for example, if you have an organ donor, you may assume that the donor is a healthy subject. It is a necessary prerequisite for organ donation."
"There are four different clinical forms of Kaposi's sarcoma," Luppi explained, spelling them out.
"First comes the classic form of KS, which affects elderly men of Mediterranean origin, including Italians, for example, and Jewish people from Israel.
"The second so-called endemic form affects the African peoples, independently of HIV infection.
"Third is the so-called AIDS KS form, which affects homosexual men from the U.S. Those HIV viruses are transmitted through sexual, especially homosexual, contact and affect people from non-endemic areas. It is not endemic in the U.S. in HIV-negative people, but the risk groups of HIV-infected people may be prevalent.
"Finally, the fourth clinical form is post-transplant Kaposi's sarcoma [P-TKS]. What is striking in P-TKS is the fact that, for example, post-transplantation infection occurs mainly in people originating from the Mediterranean area. So the global Cincinnati Tumor Transplantation Registry, recording post-transplant malignancies, notes that the patients in the U.S. are from Italy, from Africa, from Israel."
KS Affects 1 In 200 Transplant Patients
"The risk for post-transplant Kaposi's sarcoma is 400 to 500 times higher in the transplant patients than in the general population of the same ethnic origin," Luppi stated. "This means that belonging to an area of high prevalence of KS, infection is a major risk for developing post-transplant Kaposi's. If you are an organ recipient from these endemic areas, or from a non-endemic area, but you receive an organ from a donor originating from an endemic area, again, you have an increased risk of developing post-transplant KS.
"The first implication of our paper," Luppi pointed out, "concerns screening for the donor - especially in areas endemic for the prevalence of HSV infection. In some European countries, for example, such as Italy, there is a prevalence of HSV infection in the general population. But in these areas, there is no routine screening of the donor organ for HSV. So the first thing to do is to prompt such screening all over the world for the virus lurking in the donor organ.
"Immunosuppressed people - HIV-infected and organ transplant subjects - face an increased risk of developing Kaposi's sarcoma."
Here is how Luppi's team analyzed male and female donor organs:
"The idea we pursued was to examine the tumor in the recipient. We used the technique of micromanipulation, which allowed us to pick up single neoplastic cells in the tumor. The idea was if we have a male donor, and a patient who is a female, if we bet that the tumor cells are indeed from donor origin, they should harbor the genetic marker of the donor. We tried to investigate by PCR for the presence of the Y chromosome on the HSV genes, which are present in the male donor but not in the female recipient.
"And what we showed," Luppi said, "is that these markers are present in the vast majority of these tumor cells from a female recipient. Proving that most of these tumor cells are not from the recipient, as people in the field suspected, but most of them were of donor origin. Our different technical approaches showed one thing: Most of these cells harbored genetic markers and expressed antigens from the donor."
National Transplant Study Plans 300 Donors, Recipients
The co-authors are now pursuing ongoing projects.
"First of all," Luppi continued, "with the transplant group in Italy we are conducting a large national study to assess the prevalence of HSV in donors and recipients to estimate the risk of developing Kaposi's sarcoma, and to see on large numbers the issue of transmission of this virus and these virus-infected cells from the donors to recipients. This is a prospective study, so with some of the most active transplantation centers in Italy we are collecting the peripheral blood cells and sera from the donors and recipients at the time of transplantation, and looking for antibodies and the presence of DNA sequences in the peripheral blood and plasma. We'll be analyzing 300 patients consecutively.
"We plan to monitor the recipients at different time points after transplantation for recurrence of seroconversion or reactivation of this infection, and try to correlate these markers with clinical manifestation in the recipients. We projected this national study a year and a half ago when we showed the viral transmission of the donors. After that, we started these studies, which we are now completing. It will take a couple of years of patient follow-up. Occurrence of KS sets in within six to 24 months after transplantation, so we need to wait a couple of years for the possible occurrence of KS after transplantation.
"Meanwhile," he concluded, "we are investigating the topic of screening donors and recipients. Also, we are trying to develop these approaches with immunotherapy in order to find strategies to treat these patients."