ARTICLE
Auteur(s) : Şirin Yaşar, Ayse Tülin Mansur, Fatih Göktay, Ikbal Esen
Aydingöz
Haydarpaşa Numune Training and Research Hospital Department of
Dermatology, 34668 Istanbul, Turkey
accepté le 27 Septembre 2006
Kaposi sarcoma (KS) is an angiogenic-inflammatory neoplasm that
originates from vascular endothelial cells. The lesions affect the
dermis and a variety of internal organs such as lymph nodes and the
gastrointestinal tract. Human herpesvirus-8 (HHV-8) also known as
KS-associated herpes virus, has been detected in KS lesions and is
now considered to be the causal agent of all known
clinico-epidemiologic forms of KS. However, KS develops in only a
few of the HHV-8-infected individuals [1]. The development of KS is
favored by acquired immunodeficiencies, such as human
immunodeficiency virus (HIV) co-infection (epidemic) or
transplantation-related immunosuppression (iatrogenic) [2].
Case report
A 70-year-old man consulted the Department of Dermatology, for
multiple cutaneous tumoral lesions of 7 months duration. The
patient was put on regular hemodialysis, 3 times a week, for
chronic renal failure due to hypertensive nephropathy 7 months
previously. He had been on oral captopril therapy, 10 mg/day, since
that time. His past medical history was remarkable for diabetes
mellitus and hypertension, present for 5 and 6 years respectively.
The first tumoral lesion had been noticed on his left wrist, and
afterwards several similar nodules had developed rapidly.
On clinical examination, there were many dark red to violaceous,
firm, angioma-like nodules and plaques, measuring 0.5-3 cm in
diameter on his neck, face, and trunk, upper and lower extremities,
including both palms and soles (figure 1). Pathologic
studies of a nodular lesion revealed findings consistent with
nodular stage KS (figure
2). Real-Time polymerase chain reaction studies (Light
Cycler, Roche Diagnostics, Germany) were performed on one of the
biopsy specimens, and HHV-8 genome (primers specific for ORF 26
region) was detected. Routine biochemical tests were normal except
for hyperglycemia (176 mg/dL; normal range, 76-110 mg/dL), high
serum level of creatinine (8.74 mg/dL; normal range 0.6-1.5 mg/dL)
and blood urea nitrogen (83 mg/dL; normal range, 9-28 mg/dL),
high serum ferritin (573 ng/mL; normal range, 30-400 ng/mL), low
serum iron (22 μg/dL; normal range 31-158 μg/dL). Complete blood
count showed anemia with Hb 9.23 g/dL (normal range, 13.6-17.2
g/dL), and Htc 27.2% (normal range 39.5-50.3%). Erythrocyte
sedimentation rate was 38 mm/h, CRP 16.2 mg/L (normal < 5
mg/L) and urinalysis revealed proteinuria, pyuria and hematuria.
The results of the serologic tests for HIV, HCV and HBV were
negative. Computed tomography scans of the cranium, thorax and
abdomen revealed normal findings, except for bilateral renal
atrophy. There was no clinical and laboratory evidence of
immunosuppression. One week after admission, captopril was
discontinued, as his blood pressure was in normal limits. During
his hospitalization of 1 month, new lesions kept on developing on
extremities, and after withdrawal of captopril, no regression was
observed.
Discussion
It is well known that HHV-8 is consistently found in KS related
with renal transplantation. In addition, patients with iatrogenic
immunosuppression or HIV infection have been reported to display
HHV-8 positivity in their KS lesions [3]. Furthermore, in recent
years, there are several reports of non-immunosuppressed patients
with KS, also demonstrating the HHV-8 genome [4].
The case presented is another example that factors other than
iatrogenic or HIV-associated immunosuppression could contribute to
the development of KS, due to activation of HHV-8. A literature
survey showed that there are a few cases of KS associated with
hemodialysis. The first reported case was an elderly man from
Kuwait undergoing hemodialysis due to tubulointerstitial renal
disease [5]. He had concomitantly developed multicentric Castleman
disease, which is now known to be induced by HHV-8 [6].
Nevertheless, molecular analysis for HHV-8 was not carried out in
this case. The second report described two cases from Korea, who
developed KS in association with short-term dialysis. The patients
had been suffering from chronic renal failure, due to renal
tuberculosis and diabetic nephropathy, respectively. One of the
cases yielded HHV-8 sequences in skin lesions of KS, by the PCR
method [7]. A recent report presented a case of an elderly,
non-immunosuppressed male of Greek nationality undergoing dialysis,
who developed KS. HHV-8 was documented in blood and skin lesion of
KS by reverse transcriptase PCR [8].
The relation between chronic renal failure, HHV-8 and KS is not
well established. However, there are several reports indicating
various immunological abnormalities leading to impaired immune
status in uremic adults [9]. In favor of this view, the frequency
of neoplasia other than KS, including liver, colon, rectum,
thyroid, kidney, bladder, lung and lymphoid organ malignancies have
been reported to be higher in the patients undergoing dialysis than
in control groups [10].
In our patient, we do not know the exact pathogenesis of the
coexistence of KS with renal failure and dialysis; but it may be
more than coincidental. The clinical course, with the rapid
progression of KS lesions and widespread nodules and plaques mostly
prominent on the face, neck, upper extremities and trunk, seems to
be quite different from the classical KS observed in people with
Mediterranean ancestry. Moreover, the close time relation between
the initiation of dialysis and development of KS, indicates a
possible role of renal failure in the induction of the lesions. In
a recent study performed in Saudi Arabia, the prevalence of
antibodies to HHV-8 in patients with end stage renal disease,
though not statistically different, was higher than in normal
controls (6.9% versus 3.88%) [11]. However, in a study by Whitby et
al., the prevalence of antibodies against HHV-8 in hemodialysis
patients was 9.2%, which was comparable to that documented in blood
donors from northern Italy [12]. In another report, while the
prevalence of HHV-8 DNA in polymorphonuclear leucocytes was 69.6%
in patients with KS, it was found to be 23.8% in healthy controls
and patients with various non-KS dermatologic disorders [3]. These
figures suggest that HHV-8 could be a common virus, at least in
countries where KS is more prevalent. HHV-8 may have a latent
period before activation, similar to other members of herpes virus
family, and may play a role in the development of KS, in the
presence of predisposing factors [6]. Our patient had two important
systemic diseases, diabetes mellitus and renal failure, which are
known to have suppressive effects on immune responses. The elevated
serum levels of glucose with diabetes alter host immune responses,
resulting in a well-documented increase in the predisposition to
infectious processes. Moreover, the competence of the immune system
may decrease with age causing HHV-8 to escape from immunological
control. Supporting this hypothesis, a strong association between
increasing age and HHV-8 seropositivity has been demonstrated in
patients with renal failure [11].
Unfortunately, we do not have any information on the blood HHV-8
antibody levels prior to the onset of KS. The patient was referred
to our clinic from a dialysis center after the development of KS,
and we learned that HHV-8 antibody testing had not been performed
before the onset of skin lesions. If a positive result were
available, this would allow a discussion about the time related
effects of HHV-8 positivity on the evolution of KS.
Nevertheless, it is well known that even in renal transplant
recipients, not all patients who carry the virus or who demonstrate
sero-convertion will develop KS. A substantial number of patients
will carry the virus without developing the tumour [13]. It may be
speculated that, the duration of HHV-8 positivity may determine the
development of sarcomas. However, this may also indicate the
possibility of some other, yet unknown factors, including viral
load, to trigger the development of clinical disease. The relation
of the development of KS and the duration of HHV-8 positivity can
be elucidated only if sequential HHV-8 antibody testing on renal
transplant recipients with and without KS is performed in the
future.
Another interesting point of our case was the longstanding
captopril treatment, in almost the same period with KS development.
Captopril is an angiotensin-converting enzyme inhibitor, used for
treating hypertension. Another, not well-known effect of captopril
is immunosuppression, probably mediated via an influence on
lymphoid cells. A 50% reduction of lymphocytic proliferation was
observed during captopril treatment [14]. It has also been shown
that this agent inhibits the production of Th2 cytokines [15]. Some
authors speculated that prostaglandins seem to be responsible from
captopril-induced immunosuppression [16].
There are two reports of KS associated with captopril treatment.
The first patient was a 70-year-old Italian heterosexual man who
had been treated with captopril for 6 years. After 1 month of
stopping captopril, KS lesions showed a dramatic regression, and
after 3 months, no lesion was seen [17]. The other case was a
70-year-old Algerian woman with rheumatoid arthritis, who had
developed cutaneous and gastric lesions of KS after 8 months of
treatment with captopril. After withdrawal of the drug, cutaneous
and gastric lesions rapidly disappeared [18].
On the other hand, captopril also shows an antiangiogenic
effect, and this way, has been demonstrated to reduce tumor growth
in various experimental models, contrary to the above-mentioned
observations [19]. Moreover, it has been reported to inhibit
angiogenesis in KS, leading to disappearance or regressing of the
lesions [20].
In the presented case, in contrary to these reports, the lesions
had developed under the treatment of captopril, and showed no
evidence of regression after withdrawal of the drug. Therefore, it
may be speculated that, in our patient, the cumulative effect of
age-related immune senescence, immunosuppressive effects of
captopril, immune alteration due to underlying diseases, together
with HHV-8 infection, might have contributed to the pathogenesis of
KS.
As the treatment of transplant-related KS consists mainly of
dose reduction or withdrawal of immunosuppresive agents, the
patients are under serious risk for deterioration of renal function
or graft rejection. Therefore, novel therapeutic agents which will
be beneficial in regressing KS, with no deleterious effects on
graft, have been investigated. In recent years, a promising agent,
rapamycin, has been explored as an approach addressing this
problem.
Rapamycin (sirolimus) is a new immunosuppresive drug which has
been used effectively to prevent transplant rejection. It
specifically inhibits signaling from the serine-threonine kinase,
namely, mammalian target of rapamycin (mTOR) [21]. This particular
kinase acts as a key intermediary in multiple mitogenic pathways
and modulates proliferation and angiogenesis in normal and
neoplastic tissues. Rapamycin has been shown to decrease both the
number and the proliferative, migratory, adhesive and tube
formation capacities of endothelial progenitor cells [22]. The
anti-angiogenic activities of the drug are linked to a decrease in
production of vascular endothelial growth factor (VEGF), which is
one of the most potent angiogenic factors described, and to a
markedly inhibited response of vascular endothelial cells to
stimulation by VEGF [23]. Recently, it has been shown that
rapamycin inhibits metastatic tumor growth and angiogenesis in
mouse models. Furthermore, there are some reports on the
antitumoral effects of rapamycin, on several types of neoplasms
including KS. Complete regression of KS in renal transplant
patients, after conversion from cyclosporin to rapamycin, has been
reported repeteadly [24].
In conclusion, chronic renal failure requiring hemodialysis
treatment may predispose the development of KS, probably by
activation of HHV-8. The efficacy of captopril on the treatment of
KS is not clear yet. It seems that captopril has dual and
inconsistent effects on the proggression of KS. Our case is another
example which discourages its use for this specific issue. Probably
the dose, the duration of therapy and the immune status of the
patient may all determine the progression or regression of the
tumour. New anti-angiogenic drugs such as rapamycin may represent a
promising therapeutic option, especially in renal transplant
patients with KS.
Acknowledgements
Financial support: None. Conflict of interest: None.
References
1 Antman K, Chang Y. Kaposi’s sarcoma. N Engl J Med 2000;
342: 1027-38.
2 Mendez JC, Procop GW, Espy MJ, Smith TF,
McGregor CG, Paya CV. Relationship of HHV8 replication
and Kaposi’s sarcoma after solid organ transplantation.
Transplantation 1999; 67: 1200-1.
3 Cattani P, Capuano M, Lesnoni La Parola I,
Guido R, Santangelo R, Cerimele F, Masini C,
Nanni G, Fadda G, Cerimele D. Human herpesvirus 8 in
Italian HIV-seronegative patients with Kaposi sarcoma. Arch
Dermatol 1998; 134: 695-9.
4 Boneschi V, Brambilla L, Berti E,
Ferrucci S, Corbellino M, Parravicini C,
Fossati S. Human herpesvirus 8 DNA in the skin and blood of
patients with Mediterranean Kaposi’s sarcoma: clinical
correlations. Dermatology 2001; 203: 19-23.
5 Nampoory MR, Johny KV, Sarkar C,
Al-Masry I, Al-Hilali N, Anim JT. The dialysed
patient with both Castleman disease and Kaposi sarcoma. Nephrol
Dial Transplant 1998; 13: 2373-6.
6 Lebbe C. Human herpesvirus 8 as the infectious cause of
Kaposi sarcoma: evidence and involvement of cofactors. Arch
Dermatol 1998; 134: 736-8.
7 Herr H, Kim JU, Kang GH, Moon KC,
Koh JK. Kaposi’s sarcoma occurring during short-term dialysis:
report of two cases. J Korean Med Sci 2001; 16: 130-4.
8 Metaxa-Mariatou V, Chiras T, Loli A,
Gazouli M, Vallis D, Nasioulas G. Molecular analysis
of Kaposi’s sarcoma occurring during haemodialysis. Clin Exp
Dermatol 2004; 29: 188-91.
9 Remuzzi G, Schieppati A, Minetti L. Hematologic
consequences of renal failure. In: Brenner BM, Rector FC,
eds. The Kidney. Philadelphia: Saunders, 2004: 2165-88.
10 Inamoto H, Ozaki R, Matsuzaki T, Wakui M,
Saruta T, Osawa A. Incidence and mortality patterns of
malignancy and factors affecting the risk of malignancy in dialysis
patients. Nephron 1991; 59: 611-7.
11 Almuneef M, Nimjee S, Khoshnood K,
Miller G, Rigsby MO. Prevalence of antibodies to human
herpesvirus 8 (HHV-8) in Saudi Arabian patients with and without
renal failure. Transplantation 2001; 71: 1120-4.
12 Luppi M, Vandelli L, Whitby D,
Savazzi AM, Barozzi P, Medici G, Albertazzi A,
Torelli G. Human herpesvirus-8 infection in hemodialysis
patients from northern Italy. Kidney Int 1999; 55: 340.
13 Sheldon J, Henry S, Mourad M, Bodeus M,
Squifflet JP, Schulz TF, et al. Human herpes virus 8
infection in kidney transplant patients in Belgium. Nephrol Dial
Transplant 2000; 15: 1443-5.
14 Kallenberg CG, van der Laan S, de Zeeuw D.
Captopril and the immune system. Lancet 1981; 11: 92.
15 De Albuquerque DA, Saxena V, Adams DE,
Boivin GP, Brunner HI, Witte DP, Singh RR. An
ACE inhibitor reduces Th2 cytokines and TGF-beta1 and TGF-beta2
isoforms in murine lupus nephritis. Kidney Int 2004; 65:
846-59.
16 Johnsen SA, Aurell M. Immunosuppressive action of
captopril blocked by prostaglandin synthetase inhibitor. Lancet
1981; 1: 1005.
17 Puppin Jr. D, Rybojad M, de la
Chapelle C, Morel P. Kaposi’s sarcoma associated with
captopril. Lancet 1990; 336: 1251-2.
18 Larbre JP, Nicolas JF, Collet P,
Larbre B, Llorca G. Kaposi’s sarcoma in a patient with
rheumatoid arthritis possible responsibility of captopril in the
development of lesions. J Rheumatol 1991; 18: 476-7.
19 Volpert OV, Ward WF, Lingen MW,
Chesler L, Solt DB, Johnson MD, Molteni A,
Polverini PJ, Bouck NP. Captopril inhibits angiogenesis
and slows the growth of experimental tumors in rats. J Clin Invest
1996; 98: 671-9.
20 Vogt B, Frey FJ. Inhibition of angiogenesis in
Kaposi’s sarcoma by captopril. Lancet 1997; 349: 1148.
21 Rao RD, Buckner JC, Sarkaria JN. Mammalian
target of rapamycin (mTOR) inhibitors as anti-cancer agents. Curr
Cancer Drug Targets 2004; 4: 621-35.
22 Chen TG, Chen JZ, Wang XX. Effects of
rapamycin on number activity and eNOS of endothelial progenitor
cells from peripheral blood. Cell Prolif 2006; 39: 117-25.
23 Guba M, von Breitenbuch P, Steinbauer M,
Koehl G, Flegel S, Hornung M, Bruns CJ,
Zuelke C, Farkas S, Anthuber M, Jauch KW,
Geissler EK. Rapamycin inhibits primary and metastatic tumor
growth by antiangiogenesis: involvement of vascular endothelial
growth factor. Nat Med 2002; 8: 128-35.
24 Gutierrez-Dalmau A, Sanchez-Fructuoso A,
Sanz-Guajardo A, Mazuecos A, Franco A, Rial MC,
Iranzo P, Torregrosa JV, Oppenheimer F,
Campistol JM. Efficacy of conversion to sirolimus in
posttransplantation Kaposi’s sarcoma. Transplant Proc 2005; 37:
3836-8.
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