Staging of classic Kaposi’s sarcoma: a useful tool for therapeutic choices

ARTICLE

Kaposi’s sarcoma (KS) is a multiple site angiolymphoproliferative disease whose pathogenesis involves various immunological and genetic mechanisms, with HHV8 virus playing a decisive etiological role [1-4]. Four variants have so far been distinguished on the basis of clinical and epidemiological criteria: Mediterranean or classic KS (CKS), African or endemic KS, iatrogenic immunodepressive KS, and HIV-related KS [1, 4]. Staging classification systems for the different variants of the disease have been proposed by Taylor, Kriegel, Mitsuyasu, Chachowa, Krown and Volberding [5-10] on the basis of various criteria.

Our Department deals with the CKS which affects elderly subjects and has a chronic and irregular course accompanied by complications that compromise patient autonomy, although in some cases it can undergo spontaneous regression. However, among the 300 patients we have observed so far, we have found that the disease may sometimes have an acute onset and rapidly progressive course, or undergo sudden worsening that complicates a previously chronic and generally undemanding evolution [16-18]. This variability of CKS onset and course has not been adequately taken into account in previous classifications. Taylor’s first classification [5] referred to the classical, endemic and variant forms and proposed clinical, behaviour and localisation criteria considered as being common to all variants. The recognition of AIDS-related KS made it necessary to broaden the staging criteria: Kriegel suggested a 4-stage subdivision [6] that included the parameters of visceral sites and systemic involvement, whereas the classifications of Mitsuyasu [7] and Chachowa and Krown [8, 9] introduced the concept of prognosis but only referred to the epidemic variant.

In addition, the variability of CKS clinical evolution makes it often difficult to decide when and how to start systemic chemotherapy, keeping in mind that, because of the prolonged course of the disease, it could be necessary to treat the patients on several occasions. Based on our 20-year experience of the disease and very large patient population, we have identified additional clinical parameters that have been included in a new staging system which is applicable to the classic forms of KS and may represent a useful tool for therapeutic choices.

Patients and methods

Over the last twenty years we observed 300 patients, 226 males and 74 females, suffering from CKS. The mean age at the time of the first observation was 70.6 years. Approximately 40 % of the patients already had a diagnosis of KS when they were referred to our Department for staging and, if required, treatment. Once the clinical and histological diagnosis of KS had been made, the patients underwent the following protocol:

clinical photography;

physical evaluation, including a careful evaluation of the main lymph nodal sites (in the case of an increase in nodal volume, the patients were asked to undergo lymph node ultrasonography and, if necessary, biopsy);

routine blood chemistry examinations and HIV test;

HHV8 test (serology by immunoperoxidase);

chest X-ray;

ENT examination to evaluate pharyngo-oral sites;

esophagogastroduodenoscopy and, if necessary, biopsy;

rectosygmoidoscopy, except in the case of patients with angina pectoris, arrhythmias (even if treated), severe respiratory insufficiency, untreated severe arterial hypertension or previous vascular accidents (all of these patients are given an opaque clyster with a double contrast medium despite the diagnostic limitations of the procedure);

bronchoscopy and bone marrow biopsy, performed only in patients whose overall clinical data suggested possible pulmonary or bone marrow involvement.

Not all the first 100 patients underwent digestive tract endoscopy because this was not a routine procedure at the time they first came to us; some of them only underwent radiological examination.

Results

Table I summarises our staging system which includes four clinical stages:

- Stage I (maculo-nodular): small isolated angiomatous maculae and/or nodules, prevalently localised in lower limbs;

- Stage II (infiltrative): prevalent violet-grey plaque lesions involving wide areas of lower limbs, sometimes associated with a few nodules;

- Stage III (florid): exuberant angiomatous plaques and nodules, often ulcerated, involving one or more limbs;

- Stage IV (disseminated): presence of a significant number of angiomatous plaques and nodules involving other skin districts in addition to the limbs.

In Table 1, the "Evolution" column refers to the speed of disease progression (A: slow and B: rapid), with rapid being defined as an increase in the total number of nodules/plaques or in the total area of plaques in the three months following an examination. Furthermore, complications which can be present in all the stages are considered: objective ones, such as ulcerations, bleeding, lymphedema, lymphorrhea, and subjective ones, such as pain, functional grip and/or ambulatory impotence. The presence of lesions in visceral sites (the gastro-enteric tract, including the oral cavity, the lymph nodes and the lungs) is also taken into account, although internal localisation is a rare event, prevalently confined to the oral cavity and gastric area in stages III and IV.

All of the 300 CKS patients we have observed over the last 20 years have been classified according to this staging system. As shown in Table II, we observed a great number of patients suffering from the aggressive form of the disease, in particular stages III and IV. The percentage of cases at these stages is probably overestimated in our patient population. This situation can be due to the fact that general practitioners (GPs) frequently attach little importance to the condition at stages I and II and do not refer these patients, or that the patients themselves do not even take the problem to their GPs.

Table II also shows that slow evolution is predominant in the maculo-nodular and infiltrative stages (79 % and 58 % respectively), but rare in the florid stage (8 %) and absent in the disseminated stage. Conversely, rapid evolution is prevalent in the florid and disseminated stages (92 % and 100 %, respectively), but less frequent in the infiltrative stage (42 %) and relatively rare in the maculo-nodular stage (21 %). Complications can occur during all stages in case of rapidly evolving disease and are observed in most stage IIIB and IVB patients (76 % and 86 %, respectively). On the other hand, complications are absent (stage I) or infrequent (17 % in stage II and 12.5 % in stage III) in slowly evolving disease. Finally, visceral lesions occur almost only in rapidly evolving cases in the florid (1.2 %) and disseminated stages (23.5 %), with pharyngo-oral (5 cases), gastric (2 cases), pulmonary (1 case) or inguinal lymph node involvement (1 case). Based on these clinical findings, therapeutic choices have been made in our CKS patients, as summarised in Table III.

Discussion

The heterogeneity of clinical presentation and the variability of evolution of CKS make difficult the staging of the disease. As we felt it was more appropriate for CKS, we used Taylor’s classification from the late ‘70s until our growing experience indicated that it was insufficiently specific and therefore not really suitable for our requirements. Indeed, Taylor’s first classification [5] mostly referred to the African endemic form which affects young people and often runs an aggressive course with nodal and bone involvement, rarely present in CKS. Moreover, in our opinion the staging systems elaborated after the rise of AIDS-related KS [8-10] are not suitable for CKS, as the former worsens rapidly with early spreading to visceral organs in the context of severe immunodeficiency [14, 15] mostly lacking in CKS.

Furthermore, the availability of effective therapeutic tools for KS such as radiotherapy, immunotherapy, intra-lesional or systemically administered antiblastic drugs [11-13, 16-19] have often obliged us to decide whether it is justified to treat elderly patients with therapies that are not free of side effects and require constant monitoring. These considerations underline the need for objective clinical evaluation criteria that may help in decision making.

Our 20-year experience of CKS and the analysis of a large patient population brought us to highlight two parameters, i.e. the speed of evolution and the presence of complications, which, in the context of a modified disease staging, may be helpful for prognostic and therapeutic evaluations.

We have found that most of the patients with maculo-nodular (stage I) or infiltrative (stage II) disease have a slow evolution without complications, thus allowing us to avoid systemic chemotherapy administration. These patients, who can be adequately monitored by means of examinations every 2-3 months, could be treated with intralesional chemotherapy and/or elastic stockings. We prefer to avoid the use of radiotherapy, especially for lower limb lesions, in view of the potential adverse affects, such as late radiodermatitis and chronic ulcerations, due to a possible overlap of radiation fields in time and reduced limb perfusion associated with old age.

However, we do use systemic chemotherapy in the case of stage II patients with slowly evolving complicated disease or rapidly evolving disease with or without complications, and in all variants of stage III and IV disease. We employ classic chemotherapy and not interferon immunotherapy because, in our experience, the latter causes clinically significant systemic side-effects in elderly patients.

Although visceral involvement was observed almost only in stage IIIB and stage IVB patients (i.e. those with rapidly evolving florid or disseminated disease), it can also occur during other disease stages. Therefore, all patients (regardless of their disease stage) should undergo instrumental examinations aimed at identifying visceral lesions which, in any case, indicate the use of systemic therapy.

Although we recognise that the extremely variable clinical nature of CKS makes it difficult to adopt any rigorous staging procedure, and that untreated patients require periodical re-staging because of a possible worsening in their disease status, we feel that the proposed system is not only relatively simple to apply, but also provides useful therapeutic indications.

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