ARTICLE
Kaposi's sarcoma (KS) is an angioproliferative disease which has been
isolated in four different settings: classic KS, African-endemic KS, AIDS-related
KS, and iatrogenic immunosuppressive drug-associated KS. All these forms
of KS share a similar histopathology that has been divided into different
progressive stages correlating with both clinical appearance and progression
of the lesions [1-3]. Early patch-stage KS lesions are characterised by
the proliferation of small and jagged endothelial lined spaces surrounding
normal dermal vessels. The more advanced stages of KS consist of the proliferation
of spindle-shaped cells of probable vascular origin which, in time, become
the predominant phenotype.
Despite considerable research over the past few years, the pathogenesis
of KS development and histological progression is only partially known.
The question of the mono- or polyclonality of KS lesions remains controversial
[4, 5]. The multicentric origin of KS lesions, their frequent regression,
their low levels of DNA aneuploidy and their lack of nuclear atypia are
more compatible with a reactive proliferative process than with a true
neoplasia [6, 7]. Supporting the theory of a reactive polyclonal proliferation,
we and others previously demonstrated the presence of atypical dermal
vessels in clinically uninvolved skin from AIDS patients [8, 9]. As this
condition might expand the histopathological spectrum of KS lesions, Schwartz
and colleagues called it pre-KS [9]. We report here on a case of classic
KS in which atypical oedematous papules consisting of grouped capillaries
with inflammatory infiltrates were found in the neighbourhood of characteristic
purplish KS lesions. We suggest that these oedematous papules may represent
pre-KS lesions.
Case report
A 75-year-old HIV-negative Sicilian man was referred for a 1-year history
of cutaneous purplish macules, papules, nodules and plaques that had appeared
on lymphoedema of both legs. The patient was otherwise suffering from
a severe asthmatic bronchitis whose treatment was dependent on corticosteroids
(e.g., 5 to 40 mg of prednisone per day for 15 years). Skin biopsies
of the purplish macular, papular and nodular lesions confirmed the diagnosis
of KS. Closer examination of the legs showed several flesh-coloured, well-defined
papules that were scattered on oedematous, tender areas (Fig.
1). There were also similar, opalescent pink lesions with somewhat
more relief, which looked clinically intermediate between these papules
and typical KS lesions (Fig. 2).
Routine haematoxylin-eosin examination revealed a prominent oedema of
the dermis with endothelial lined spaces surrounded by lymphocytes and
plasma cells (Figs. 3
and 4). Using hot-start PCR amplification with KS 330-233
primer sequences [10, 11], we identified human herpesvirus 8 (HHV-8) genomes
not only in the purplish papular and nodular lesions but also in the oedematous
papules. By contrast, histologically normal skin (arm) did not produce
amplified HHV-8 DNA. Semi-quantitative analysis of the bands revealed
that the HHV-8 load was somewhat lower in the oedematous papule than in
typical purplish papular or nodular lesions (Fig.
5).
KS-cell cultures were derived from an atypical
oedematous papule and from an adjacent nodular lesion and were established
similarly as previously described [12, 13]. Briefly, the cells were grown
without additional growth factors in minimum essential medium D-Val (Gibco,
Paisely, Scotland) containing 10% inactivated fetal calf serum (FCS) (Gibco),
1% non-essential amino acids, penicillin (100 U/ml) and streptomycin (100
µg/ml). Cells derived from both cultures had the same morphology
(spindle-cell appearance) and showed an immunophenotype similar to that
described for KS cells (positivity for laminin, vimentin, collagen IV,
alpha-smooth muscle actin, ICAM-1, and negativity for keratin, ICAM-2,
ELAM-1, VCAM-1, CD 34, CD 40) [12-14].
Discussion
KS presents with a variety of morphological patterns, depending noticably
on the histological stage of the lesion [2]. The usual clinical presentation
of the early "patch-stage" KS consists of opalescent pink to red, or purple,
macules. The clinical correlate of more advanced stage KS lesions usually
consists of red to purplish-brown papules, nodules, or plaques. We report
here on atypical flesh-coloured oedematous papules that were characterised
histologically by the presence of lymphocytic infiltrates and by the proliferation
of grouped, rather thick-walled capillaries. We suggest that such lesions
may represent pre-KS lesions. Several lines of evidence may support this
hypothesis: 1) HHV-8 DNA sequences were found in the atypical oedematous
papules and in the characteristic purplish lesions but not in histologically
normal skin. We cannot formally exclude that the isolation of HHV-8 in
these oedematous papules could have come from infected peripheral blood
mononuclear cells circulating (PBMC) to the skin. The absence of HHV-8
in uninvolved skin does not favour the hypothesis of a "contamination"
of the papules by circulating HHV-8-positive PBMC. However, it remains
possible that the lesions studied are positive because of
their blood-borne lympho-plasmatocytic infiltrate, absent from normal
skin. Supporting other studies, these data suggest that the detection
of HHV-8 may serve as a useful tool in distinguishing atypical and/or
early KS lesions from non-KS lesions [15-16]. Alternatively, the presence
of HHV-8 DNA sequences in those early oedematous lesions suggests that
the vascular proliferation seen in the "patch-stage" KS lesions may be
an early consequence of the infection of vascular cells by the virus.
2) The cells derived from the oedematous papules showed morphological
and immunophenotypical features similar to those reported for KS-derived
spindle cells. This supports the hypothesis of an effective selection
of specific cells with a phenotypic advantage among the heterogeneous
populations making up the lesions. Confirming other studies, we found
that, contrary to KS cells in situ, the KS-derived spindle cells
do not express CD34 and CD40 antigens [12-14, 17]. The significance of
these findings remains unclear. The disappearance of HHV-8 [18, 19] and
of the lymphokine-rich environment of KS lesions under culture conditions
are possible explanations for these apparent discrepancies. 3) Lymphoedema
may cause various cutaneous changes, including a hyperkeratotic and warty
appearance of the epidermis, fissures, secondary infections or tumours
[20, 21]. We are not aware of the description of such oedematous, well-defined
papules in the spectrum of lymphoedema-associated skin changes. These
lesions were clinically different from lymphangiectases by their firm
consistence. In addition, they were not translucent, and their puncture
did not provoke the flow of a milky liquid.
In conclusion, our data support the existence of a pre-KS stage that
may expand the clinico-pathological spectrum of KS lesions. Lymph-angiogenesis
is an early manifestation of lymphatic obstruction and as KS may arise
on areas of chronic oedema [22, 23], we suggest that in predisposed (presumably
HHV-8 infected) individuals, oedema formation may be involved in the induction
of such lesions.
CONCLUSION
Acknowledgements
This work was partly supported by a grant awarded by the Erasme Foundation.
REFERENCES
1. Chor PJ, Santa Cruz DJ. Kaposi's sarcoma: a clinico-pathologic review
and differential diagnosis. J Cutan Pathol 1992; 19: 6-20.
2. Tappero JW, Conant MA, Wolfe SF, Berger TG. Kaposi's sarcoma. Epidemiology,
pathogenesis, histology, clinical spectrum, staging criteria and therapy.
J Am Acad Dermatol 1993; 28 : 371-95.
3. Calonje E, Wilson-Jones E. Vascular tumors. Tumors and tumors-like
conditions of blood vessels and lymphatics. In: Histopathology of the
skin (Lever's). Philadelphia, Lippincot-Raven, 1997: 889-932.
4. Rabkin CS, Siegfried J, Lash A, et al. Monoclonal origin of
multicentric Kaposi's sarcoma lesions. N Engl J Med 1997; 336:
988-93.
5. Gill PS, Tsai YC, Rao AP, et al. Evidence for multiclonality
in multicentric Kaposi's sarcoma. Proc Natl Acad Sci USA 1998;
95: 8257.
6. Simonart T, Noel JC, Van Vooren JP, et al. DNA diploidy in
AIDS-related and steroid-induced Kaposi's sarcoma. Br J Dermatol
1997; 136: 804.
7. Fukunaga M, Silverberg SG. Kaposi's sarcoma in patients with acquired
immune deficiency syndrome. Cancer 1990; 66: 758-64.
8. De Dobbeleer G, Godfrine S, André J, Ledoux M, De Maubeuge
J. Clinically uninvolved skin in AIDS: evidence of atypical dermal vessels
similar to early lesions observed in Kaposi's sarcoma. J Cutan Pathol
1987; 14: 154-7.
9. Schwartz JL, Muhlbauer JE, Steigbigel RT. Pre-Kaposi's sarcoma. J
Am Acad Dermatol 1984; 11: 377-380.
10. Chang Y, Cesarman E, Pessin MS et al. Identification of herpesvirus-like
DNA sequences in AIDS-associated Kaposi's sarcoma. Science 1994;
266: 1865-9.
11. Noel JC, Hermans P, André J, et al. Herpesvirus-like
DNA sequences and Kaposi's sarcoma. Relationship to epidemiology, clinical
spectrum, and histologic features. Cancer 1996; 77: 2132-6.
12. Benelli R, Repetto L, Carlone S, Parravicini C, Albini A. Establishment
and characterization of two new Kaposi's sarcoma cell cultures from an
AIDS and a non-AIDS patient. Res Virol 1994; 145: 251-9.
13. Blankaert D, Simonart T, Van Vooren JP, et al. Constitutive
release of metalloproteinase-9 (92-kDa type IV collagenase) by Kaposi's
sarcoma cells. J Acq Immun Def Synd 1998; 18: 203-9.
14. Pammer J, Plettenberg A, Weninger W, et al. CD40 antigen
is expressed by endothelial cells and tumor cells in Kaposi's sarcoma.
Am J Pathol 1996; 148: 1387-96.
15. Cathomas G, McGandy CE, Terracciano LM, Itin PH, De Rosa G, Gudat
F. Detection of herpesvirus-like DNA by nested PCR on archival skin biopsy
specimens of various forms of Kaposi sarcoma. J Clin Pathol 1996;
49: 631-3.
16. Dictor M, Rambech E, Way D, Witte M, Bendsöe N. Human herpesvirus
8 (Kaposi's sarcoma-associated herpesvirus) DNA in Kaposi's sarcoma lesions,
AIDS Kaposi's sarcoma cell lines, endothelial Kaposi's sarcoma simulators,
and the skin of immunosuppressed patients. Am J Pathol 1996; 148:
2009-16.
17. Kaaya EE, Parravicini C, Ordonez C, et al. Heterogeneity
of spindle cells in Kaposi's sarcoma: comparison of cells in lesions and
in culture. J Acq Immun Def Synd 1995; 10: 295-305.
18. Lebbe C, de Cremoux P, Rybojad M, Costa da Cunha C, Morel P, Calvo
F. Kaposi's sarcoma and new herpesvirus. Lancet 1995; 345: 1180.
19. Simonart T, Noel JC, Liesnard C, et al. Kaposi's sarcoma
and herpes 8 virus: a word of caution. Dermatology 1996; 193: 272.
20. Coffman JD. Cutaneous changes in peripheral vascular disease. In:
Dermatology in general medicine. Fitzpatrick TB, Eisen AZ, Wolff
K, Freedberg IM, Austen KF, eds. McGraw-Hill, Inc, 1993: 2077-104.
21. Lister RK, Black MM, Calonje E, Burnand KG. Squamous cell carcinoma
arising in chronic lymphoedema. Br J Dermatol 1997; 136: 384-7.
22. Ruocco V, Astarita C, Guerrera V, Lo Schiavo A, Moscariello CG,
Satriano RA, Pisani M. Kaposi's sarcoma on a lymphedematous immunocompromised
limb. Int J Dermatol 1984; 23: 56-60.
23. Olszewski W. On the pathomechanism of development of postsurgical
lymphedema. Lymphology 1973; 6: 35-51.
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