ARTICLE
In general, three major forms of Kaposi's sarcoma (KS) are recognised:
classical KS, a non-aggressive form without lymph node or intestinal involvement,
mostly occurring in elderly men in the Mediterranean area; endemic African
KS consisting of several subtypes with varying degrees of aggressiveness,
and KS associated with immunodeficiency, in particular AIDS-associated
epidemic KS which is characterised by early secondary spread and involvement
of internal organs.
Recently an association between a new Herpes virus and classical,
endemic and AIDS-associated epidemic KS was demonstrated by the detection
of specific DNA sequences of this virus in tumour specimens [1-4]. The
infective agent, referred to as human Herpes virus type 8 (HHV-8)
or Kaposi's sarcoma-associated Herpes virus (KSHV), was also found
in mononuclear cells in the peripheral blood of patients with KS as well
as in uninvolved skin from the majority of patients with classical and
epidemic KS [1, 5]. The presence of HHV-8 in the skin of healthy controls
is still controversial [2, 3]. HHV-8 antibodies were detected in the sera
of most patients with epidemic KS and in the sera of all patients with
classical KS [6].
We describe an 82-year-old male patient from Saxony (East Germany) with
classical KS who, during World War II, had served on the Greek Islands
of Crete and Rhodes but who had not left East Germany again after 1945.
This allows us to make a tentative estimation of the incubation period
in classical KS.
Case report
The 82 year-old patient had developed erythematous plaques and nodules
as from 1986. He had been on active service on Crete and Rhodes in 1941/42
and 1943/44 respectively. The patient denied having had sexual intercourse
there. After his return to Saxony, he remained in East Germany because
of political restrictions. The patient first developed a bluish-red nodule
on his left lower leg in 1986. This nodule was excised and diagnosed as
KS. The patient tested HIV negative and there was no internal involvement.
Thus, a diagnosis of classical KS was made.
At the time of attending our clinic, the patient was found to have multiple,
brown-bluish-red plaques and a number of soft tumours. There was some
association of the lesions with skin lines on the trunk (Fig.
1), the face was entirely free of skin changes. There was also
no involvement of the oral cavity and no tumours were detected on gastroscopy.
Investigations for HIV 1 and HIV 2 antibodies were again negative. The
syphilis serology too was negative. The patient claimed never to have
had homosexual intercourse. CMV (228 AE/ml) and EBV (1:640) IgG antibodies
were elevated but there were no IgM antibodies. CD4+ and CD8+
counts were normal as was their ratio (1.6). Only 2.7% of lymphocytes
and 54.4% of monocytes expressed HLA-DR antigens. The reaction
to recall antigens (Merieux Multitest) was normal. The histocompatibility
type was HLA-A01, A24, B08, B49, Bw4, Bw6, CW07, HLA-DR-B1*1501, 1101,
DQ-B1*0602, 0301, DP-B1*0402, 0402.
Biopsy specimens were digested in 400 ml "melting
buffer" (50 mM Tris-Hcl pH 8.0, 100 mM EDTA, 0.5% SDS, Proteinase K 0.5
mg/ml) at 37° C for 8 hours. The reaction mixture
was extracted with phenol/chloroform/isoamylalcohol (50:49:1) twice and
the DNA precipitated with ethanol. One mg of DNA was subjected to 35 PCR-cycles.
The amplification reaction was performed in a total volume of 50 ml using
1.25 units of Taq DNA polymerase (Perkin-Elmer), 100 mM dNTP, 3 mM MgCl2,
10 mM Tris-HCl (pH 8.3), 50 mM KCl, 0.001% gelatine, and 50 pmol of both
primers KS802 (5'cgg act aca tcc aaa tta tgc ag) and KS1263 (5' ggt aca
tgg aca gat cgt caa g3'). An initial denaturation step (95°
C 4 min) was followed by 35 amplification cycles (95°
C 30 sec, 60° C 30 sec, 72° C 1 min). Two ml
of each PCR reaction were reamplified in a 50 ml nested-reaction with
oligonucleotides KS983 (5' ttt tag ccg aaa gga ttc cac c3') and KS1221
(5' gat ccg tgt tgt cta cgt cca g3') using the reaction conditions described
above. Ten ml of each PCR reaction were separated on a 1.2% agarose gel
and visualised by fluorography. The expected size of first and second
round reaction products was 461 bp and 283 bp, respectively. With
this method HHV-8 DNA sequences were detected in a biopsy from a typical
KS lesion on the trunk (Fig. 2)
but not in a biopsy from normal skin or in peripheral blood mononuclear
cells.
The patient was seropositive for HHV-8 antibodies (IgG). His spouse
had died several years earlier and his son was not available for testing.
Discussion
HHV-8 DNA sequences have been detected in 50 to 100% of tumour specimens
from patients with classical KS [1, 3, 4, 7]. Such sequences were also
found in a biopsy from a KS lesion in our patient while his normal skin
was negative for HHV-8 DNA. In a recent report, 4/7 specimens from uninvolved
skin of patients with classical KS were positive [1]. In patients with
epidemic AIDS-associated KS, HHV-8 DNA was detected in 35-91% of leucocytes,
no such DNA sequences were found in our patient [5, 8, 9].
The development of KS in HHV-8 positive AIDS patients seems to depend
on a decrease of CD4+ lymphocytes to below 400/ml, our patient
had normal CD4+ counts and a normal CD4+/CD8+
ratio confirming the diagnosis of classical KS [5, 9]. The relationship
between HLA antigens and classical KS is controversial. Neither HLA-DR5,
HLA-DR4, HLA-DR12 or HLA-B18 which are thought to be associated with classical
KS in populations in Israel and Greece were present in out patient [10,
11].
Classical KS is much more frequent in Mediterranean areas of Europe
and in Israel than in Northern and Western Europe, Australia or the USA
[12]. Before the advent of HIV infection, the incidence rate of classical
KS was 10.3 per 100,000 males above the age of 50 and about 1.8 per 100,000
in the general population in Southern Italy [13]. Increased
incidence rates of classical KS were also observed in immigrants
from Southern Europe in Los Angeles, Great Britain and Denmark [7, 14-16].
Correspondingly, the prevalence of HHV-8 antibodies was reported to be
4% (4/107) in Italian blood donors and 0% (0/122) in blood donors in North
America while in Uganda more than 50% of HIV-negative patients without
KS were found with HHV-8 antibodies [6]. On the other hand,
using a more sensitive, but probably slightly less specific assay,
other investigators found a prevalence of HHV-8 antibodies in 25%
in the American general population [17].
So, although the epidemiological situation concerning
the human Herpes virus type 8 is not entirely clear yet, we assume
that our patient, who spent 4 years on active service in a Mediterranean
area and who did not leave Saxony (East Germany) after 1945, was probably
HHV-8 infected in the early forties and that it was at least 40 years
before the first tumour of his classical KS appeared. A different place
and time of infection appear to be unlikely although no old serum
from this patient exists to enable us to completely rule out a later date
of infection. The obligatory cancer registry of the former German Democratic
Republic (GDR) recorded 11 cases of KS in a population of 17 million during
the period 1961 to 1990. Only one of these was probably HIV related. This
allows us to calculate an approximate incidence rate of classical KS in
this part of central Europe of 0.002 per 100.000 again making a
locally acquired infection extremely unlikely.
In two AIDS patients, the appearance of KS was noted 3 years after HHV-8
seroconversion while another three were HHV-8 seropositive for at least
8-10 years before a diagnosis of KS was made [9]. Although there are only
few reports of long term follow-up of patients with classical or epidemic
KS, it seems reasonable to assume that KS due to HHV-8 infection has considerably
shorter incubation periods in immunocompromised patients than in otherwise
healthy individuals.
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