Nella casistica complessiva delle 259 pazienti con carcinoma endometrioide dell’endometrio, la percentuale di ricaduta è stata del 13.9% e la maggior parte di esse erano a distanza. Questi dati sono in accordo con la letteratura (Tabella 11, 106-112). In uno studio multicentrico retrospettivo italiano comprendente 1616 casi di carcinoma dell’endometrio trattati presso i dipartimenti di Ginecologia e Ostetricia delle Università di Brescia, Pisa, Torino, Padova e Milano Bicocca, 209 (13%) sono andate incontro a recidiva della neoplasia (113). La sede di recidiva era la vagina in 35 casi (16.7%), la pelvi in 67 (32.1%), e a distanza in 107 (51.2%). La maggior parte delle pazienti recidivavano entro 24 mesi. Novantaquattro (45%) hanno recidivato entro un anno e quarantatre (20.6%) tra 1 e 2 anni.
I dati della letteratura hanno mostrato come il rischio di recidiva a distanza sia tra il 4% (7, 27, 107-109, 113-116) ed il rischio di ricaduta isolata a distanza si attesti tra il 4% ed il 6% (115). Tuttavia Corn e coll. hanno suggerito che il controllo loco- regionale potrebbe prevenire le recidive a distanza (116).
Una recente meta-analisi di quattro studi randomizzati (60) ha mostrato che l’aggiunta di radioterapia esterna pelvica alla chirurgia riduceva il tasso di recidive loco-regionali ma non quello di recidive a distanza o di morte per carcinoma dell’endometrio o da tutte le cause. Una meta-analisi simile di cinque studi (27, 56, 117-119) ha mostrato, in particolare, che l’aggiunta della radioterapia adiuvante esterna è dannosa nelle pazienti a basso rischio (malattia in stadio Ia-Ib e grado 1) poichè associata ad una riduzione dell’Odds ratio [OR] per la sopravvivenza totale
(0.71; 95% CI 0.52-0.96) mentre non altera la sopravvivenza per le pazienti a rischio intermedio (malattia in stadio Ic e grado 1-2 o in stadio Ib e grado 3) (OR 0.97; 95% CI, 0.69-1.35), ed offre invece, come già visto, un vantaggio in termini di sopravvivenza per le pazienti ad alto rischio (malattia in stadio Ic e grado 3) (OR 1.76; 95% CI 1.07-2.89) (120). Con questo studio si confermava che la radioterapia adiuvante esterna non riduce il rischio di metastasi a distanza (OR, 1.58; 95% CI 1.07-2.35). Per quanto riguarda il ruolo della chemioterapia adiuvante (121, 122) così come quello della chemio-radioterapia adiuvante sequenziale e concomitante nel carcinoma dell’endometrio ad alto rischio è ancora controverso (123, 124).
Di estrema importanza l’identificazione alla chirurgia di variabili patologiche predittive di un alto rischio di recidive a distanza con lo scopo di selezionare un gruppo di pazienti adatte per una chemioterapia adiuvante seguita o meno da irradiazione esterna.
A tale proposito alcuni autori hanno riportato che la profondità di invasione del miometrio è fortemente predittiva della recidiva a distanza (17, 114, 125, 126).
Mariani e coll. (126) hanno revisionato le cartelle cliniche di 229 pazienti con carcinoma endometriale in stadio I chirurgico trattato con laparoisterectomia totale, salpingo-ovariectomia bilaterale e linfadenectomia pelvica lombo-aortica con negatività istologica dei linfonodi. Dopo un follow-up mediano di 83 mesi, sono andate incontro a recidiva 22 pazienti (10% dei casi). La recidiva era vaginale in 7 pazienti, distanza in 14 casi, sia pelvica che a distanza in una paziente. Una recidiva ematogena è stata osservata in 12 pazienti e, in particolare, risultava interessato il
polmone in 7 casi, fegato in un caso, polmone, fegato e addome insieme in una paziente, polmone e linfonodi lombo-aortici in un caso, polmone, cute, encefalo e linfonodi lombo-aortici in una paziente e infine surreni più linfonodi lombo-aortici in un caso. È degno di nota che nessuna delle dieci pazienti negative per recidiva ematogena a distanza avessero avuto un’invasione miometriale ≥ 66%, rispetto alle 10 (83%) delle 12 pazienti che avevano sviluppato tale tipo di recidiva (p< 0.001). All’analisi univariata la percentuale di recidiva a 5 anni è risultato essere correlata all’invasione miometriale (≥ 66% contro < 66%, 29% contro 2%, p<0.001), lo stato degli spazi linfo-vascolari (positivo contro negativo, 16% contro 6%, p= 0.02), e il diametro del tumore primitivo (>2 cm contro ≤ 2 cm, 8% contro lo 0%, p= 0.008) ma l’analisi multivariata ha mostrato che l’invasione miometriale ≥ 66% era l’unico fattore predittivo indipendente per le recidive a distanza (RR, 24.89; 95% CI 6.52-94.99, p<0.001).
Per quanto riguarda la frequenza di positività degli spazi linfo-vascolari nel carcinoma endometriale, varia dal 4% al 36% (28, 125-136) e pochi dati sono attualmente disponibili in letteratura circa la relazione tra l’interessamento degli spazi linfo- vascolari e le recidive a distanza per via ematogena (125).
Questo reperto è associato ad un aumentato rischio di metastasi linfonodali e ad uno sfavorevole esito clinico (28, 125, 127-130, 132-135, 137).
Nel nostro studio il grado FIGO 3, l’interessamento del terzo esterno del miometrio e l’interessamento degli spazi linfo-vascolari sono risultate tutte variabili significativamente predittive delle recidive ematogene a distanza all’analisi univariata.
Questi fattori sono strettamente correlati tra di loro, poichè i tumori G1 e G2 tendono ad essere meno invasivi e ad avere un minore interessamento linfo-vascolare, mentre i tumori G3 sono spesso profondamente invasivi ed hanno una maggiore frequenza di interessamento degli spazi linfo-vascolari (132). Infatti alla regressione logistica multipla abbiamo ottenuto che soltanto la profondità di invasione miometriale e l’interessamento degli spazi linfo-vascolari sono variabili predittive indipendenti per recidiva ematogena a distanza.
Nella maggior parte degli studi la profondità di invasione del miometrio è riportata, in accordo con la classificazione FIGO, come < o ≥ 50% (1, 56, 106, 112, 113, 114, 118. 122, 123, 130, 131, 135, 138).
Tuttavia i nostri dati, in accordo con quelli di Mariani e coll. (126), sembrano consigliare di classificare l’invasione miometriale come terzo interno, terzo medio e terzo esterno. Per concludere le pazienti con tumore dell’endometrio di tipo endometrioide in fase iniziale con invasione del terzo esterno del miometrio e/o interessamento degli spazi linfo-vascolari dovrebbero essere incluse in studi randomizzati disegnati per di valutare il ruolo della chemioterapia adiuvante sola o in combinazione con la radioterapia esterna pelvica sequenziale e/ o concomitante.
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