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Mastopatia fibrocistica
di Tatjana Volpicelli
La mastopatia fibrocistica (detta anche displasia mammaria benigna o m. di Reclus dal nome del medico che la descrisse per la prima volta nel 1883) é una patologia caratterizzata da iperplasia-fibrosi dello stroma e dalla proliferazione e dilatazione dei dotti e lobuli mammari con la conseguente 
formazione di micronodulia e piccole (2-20 mm) cisti sierose (WHO 1984). Tali formazioni si evidenziano alla palpazione come piccoli noduli di consistenza variabile e facilmente spostabili alla digitopressione. Entrambe le mammelle sono interessate particolarmente nei quadranti supero-esterni e solco sottomammario.
formazione di micronodulia e piccole (2-20 mm) cisti sierose (WHO 1984). Tali formazioni si evidenziano alla palpazione come piccoli noduli di consistenza variabile e facilmente spostabili alla digitopressione. Entrambe le mammelle sono interessate particolarmente nei quadranti supero-esterni e solco sottomammario.Etiologia: non completamente chiarita. Lo sviluppo della mastopatia fibrocistica sembra legata all’attività endocrina steroidea. La malattia infatti tende a ridursi dopo la menopausa. Gli estrogeni stimolano il tessuto mammario: i vasi sanguigni si dilatano, le ghiandole ed i dotti mammari si ingrossano, si accumula liquido che, strozzato nei dotti e nei lobuli dalla fibrosi interstiziale, determina gonfiore, edema e dolenzia mammaria. Dopo la fine della mestruazione il gonfiore mammario diminuisce e le mammelle sono meno tese e nodulari. Per questo motivo il momento migliore per effettuare l’esame del seno è quello immediatamente successivo al periodo mestruale ed è necessario ripetere sempre l’esame clinico e strumentale della p/te dopo 7-10 giorni per confermare la diagnosi. Molti altri ormoni come la prolattina, il TSH, il GH, l’insulina, e il β-TGF hanno un ruolo di cofattori etiologici nell’insorgenza e mantenimento della mastopatia f.c..
Si presuppone che esista anche una certa predisposizione congenita della ghiandola. Molto spesso c’é familiarità per la mastopatia f.c..
Il diabete mellito di tipo I ha una sua importanza nella insorgenza della mastopatia f.c che assume una sua propria specifica denominazione: mastopatia diabetica ed è fonte di confusione con il cancro della mammella (2).
Frequenza: è molto diffusa (60-70%) tra le pazienti in età fertile (18-45 anni). Proprio per la sua diffusione, molti studiosi non la definiscono più una malattia, ma una piuttosto una “situazione costituzionale”.
Diagnosi:
1 -anamnesi familiare e personale: risulta dall’anamnesi familiare e personale: quasi sempre è presente una familiarità per tale patologia. Spesso sono presenti nel parentado casi di patologia neoplastica.
2 – sintomatologia: le pazienti riferiscono ipersensibilità mammaria e mastalgia modesta, ma continua e fastidiosa, che si accentua in periodo pre-mestruale.
3 – esplorazione mammaria: esplorazione cutanea della mammella rivela tumefazioni, ulcerazioni o retrazioni a buccia di arancia. Una moderata pressione sul capezzolo serve a rilevare una eventuale secrezione mammaria di latte o pus. La palpazione mammaria va eseguita dal medico delicatamente con il palmo della mano aperta su paziente adagiata in posizione supina, e mai seduta. la palpazione va iniziata dai quadranti mediali della mammella e con il braccio omolaterale della paziente ripiegato dietro la nuca. Per eseguire la palpazione dei quadranti laterali invece si richiede alla paziente di tenere il braccio lungo il fianco. Nella mastopatia f.c. si apprezzano piccole formazioni rotondeggianti di consistenza fibro-elastica (cisti) oppure noduli di consistenza dura come grani di polistirolo espanso o strie fibrose. Di tutte queste formazioni occorre valutare la mobilità rispetto alla cute sovrastante, ai tessuti circostanti e rispetto alla fascia profonda del muscolo pettorale. Le lesioni della mastopatia f.c. sono mobili, “fluttuanti” e ciò assicura della loro natura assolutamente benigna. La fissità alla cute invece è caratteristica non solo delle lesioni maligne ma anche di lesioni benigne come l’ectasia duttale e il granuloma lipofagico.
La palpazione dei linfonodi deve essere effettuata con la paziente seduta ed il braccio omolaterale abdotto di 45°. La mano del medico va introdotta nel cavo ascellare dal basso in alto comprimendo i linfonodi contro la parete ossea per poterli meglio valutare.
Autopalpazione del seno: è una pratica che le donne dovrebbere svolgere almeno una volta al mese secondo le indicazione dell’American Cancer Society.
DIAGNOSTICA STRUMENTALE:
a) – la mamm
ografia e la MRI-mammografia è quasi sempre indispensabile ed ha una sensibilità di circa l’80%. Si possono evidenziare (foto 1) aumentata densità mammaria, macrocalcificazioni (diametro > 0,5 mm), cisti, adenosi sclerosante, ectasia duttale, lipomi. Le microcalcificazioni (diametro < 0,5 mm) che sono presenti in circa il 50% delle p/ti con malattia fibrocistica (3). Microcalcificazioni si ritrovano anche nel 20% circa delle p.ti con carcinoma in situ. Nelle pazienti giovani la mammografia è associata a potenziali danni (1).
ografia e la MRI-mammografia è quasi sempre indispensabile ed ha una sensibilità di circa l’80%. Si possono evidenziare (foto 1) aumentata densità mammaria, macrocalcificazioni (diametro > 0,5 mm), cisti, adenosi sclerosante, ectasia duttale, lipomi. Le microcalcificazioni (diametro < 0,5 mm) che sono presenti in circa il 50% delle p/ti con malattia fibrocistica (3). Microcalcificazioni si ritrovano anche nel 20% circa delle p.ti con carcinoma in situ. Nelle pazienti giovani la mammografia è associata a potenziali danni (1).b) -Ecografia: ha una sensibilità dell’80-90% ed è il mezzo più accurato per in
dividuare le macrocisti. La sua sensibilità nell’individuare il carcinoma è di circa il 70%. Le cisti (fig. 3) si presentano come immagini rotondeggianti, avascolari, anecogene con rinforzo della parete posteriore e coni d’ombra bilaterali. Le cisti di diametro >3 cm si ritrovano in genere solo nelle pazienti >30 anni (4) e presentano un contenuto di alti livelli di prolattina ed ormoni steroidei (7). I noduli invece si presentano come immagini ipoecogene, irregolarmente tondeggianti, a margini sfumati.
dividuare le macrocisti. La sua sensibilità nell’individuare il carcinoma è di circa il 70%. Le cisti (fig. 3) si presentano come immagini rotondeggianti, avascolari, anecogene con rinforzo della parete posteriore e coni d’ombra bilaterali. Le cisti di diametro >3 cm si ritrovano in genere solo nelle pazienti >30 anni (4) e presentano un contenuto di alti livelli di prolattina ed ormoni steroidei (7). I noduli invece si presentano come immagini ipoecogene, irregolarmente tondeggianti, a margini sfumati.c) – L’agoaspirazione con ago sottile, 21-25 G, (Fine-needle aspiration cytology, FNAC), introdotto per la prima volta in USA nel 1950 circa. Permette di aspirare il liquido dalle formazioni cistiche. La sua sensibilità per la diagnosi di proliferazione epiteliale non atipica è dell’80-
90% e per la diagnosi di cancro del 90-95%. L’agoaspirato si esegue agevolmente presso strutture attrezzate per effettuare la puntura con tecnica sterile (ambulatori, reparti di ospedali, laboratori di analisi). Può essere eseguito senza anestesia, dal momento che comporta solo il lieve dolore della puntura con ago, oppure in anestesia locale, a seconda del tipo di ago utilizzato e della procedura adottata. Dopo aver fatto stendere la paziente su un lettino, il medico localizza tramite ecografia la sede precisa in cui effettuare il prelievo, quindi disinfetta la cute e inserisce l’ago. L’aspirazione del liquido da esaminare può avvenire manualmente, per mezzo di una normale siringa, o collegando l’ago a un apposito aspiratore. La procedura può durare, a seconda dei casi, da pochi minuti a un quarto d’ora. Al termine dell’esame la paziente può allontanarsi dall’ambulatorio autonomamente. L’esame è un po’ doloroso ma in genere il 
dolore è sopportabile. L’anestesia locale è consigliata nei soggetti particolarmente ansiosi. Il materiale prelevato viene poi adeguatamente preparato e inviato ai reparti di anatomia patologica. La FNAC è più accurata quando sono disponibili citologi esperti e quando viene eseguita una valutazione immediata da parte dei citologi per la valutazione dell’adeguatezza del materiale aspirato, in modo che possano essere eseguite subito ulteriori aspirazioni quando necessario. Sul liquido aspirato dalle cisti occorre sempre dosare il livello di estradiolo, progesterone, testosterone, DHEA, DHEA-s e prolattina; un aumentato livello di tali ormoni depone per una metaplasia apocrina dei lobuli ed un aumentato rischio di evoluzione neoplastica maligna della mastopatia f.c. (7). In presenza di difetti della coagulazione o nei soggetti in trattamento anticoagulante l’esecuzione di un agoaspirato comporta il rischio di emorragia. In questi casi è necessario valutare attentamente il rapporto rischio beneficio prima di prescrivere l’esame (8-23).
d) Core Needle Biopsy (CNB): Utilizzando un ago del diametro di 14-16 G e a multifori taglienti è possibile aspirare, sotto guida ecografica, oltre al liquido cistico, anche frustoli di tessuto dal “cuore” della lesione per un esame citologico e istologico. L’approccio alla lesione deve essere il più parallelo possibile alla parete toracica per evitare il pneumotorace. Inoltre il trasduttore deve essere orientato parallelamente all’ago per facilitarne la visualizzazione.
E’ importante penetrare all’interno della massa in esame per evitare di aspirare materiale perilesionale oltre a quello lesionale. In caso di difficoltà di penetrazione si dovrà optare per aghi del diametro di 14 G e con punta a forma di diamante.Le complicanze della CNB sono rari e non significative. Sia gli ematomi che le infezioni sono molto rari e rappresentano <1/‰ biopsie, essendo simili alle complicazioni di altri dispositivi per biopsia percutanea. Esiste la possibilità di pneumotorace, ma è molto raro e si verifica solo se si usa la tecnica a mano libera e un approccio orizzontale. Una complicanza di tutte le biopsie percutanee è lo spostamento epiteliale osservato nel 30% di tutte le biopsie. Tuttavia, le cellule spostate non sembrano essere vitali (24-32).
e) – Biopsia mammaria escissionale (open breast biopsy): la mastopatia fibrosa è caratterizzata da involuzione prematura dei lobuli e ialinizzazione 
del connettivo lasso interlobulare. Una eventuale infiltrazione peristromale è patognomonico di mastopatia f.c. diabetica (33-40).
del connettivo lasso interlobulare. Una eventuale infiltrazione peristromale è patognomonico di mastopatia f.c. diabetica (33-40). Diagnosi differenziale, va attuata nei confronti di:
– grosse mammelle pendule che stirano i legamenti ed i tronchi nervosi
– le nevralgie intercostali dovute a spondilite, obesità, infezioni respisratorie, tosse persistente
– patologia delle giunzioni costo-condrali che dà irradiazione dolorose al tessuto mammario
– talune cicatrici da biopsia
– traumatismi ripetuti
– disturbi di natura psicosomatica.
Il rischio di sviluppare una neoplasia maligna in una donna con malattia fibrocistica viene giudicato di 2-4 volte superiore al rischio di una paziente controllo. Sarebbero particolarmente pericolose le lesioni iperplastiche dell’epitelio duttale, in particolare se atipiche e localizzate non in entrambe le mammelle (5) e/o la presenza di cisti con diametro >3 cm (7). In tal caso si deve prendere in considerazione un procedimento di exeresi tanto più se la paziente presenta altri fattori di rischio per il tumore (anamnesi familiare di cancro mammario, nulliparità, quadri mammografici e termografici indicativi di una tendenza alla neoplasia maligna (6).
Istologia: La mastopatia cistica è caratterizzata da iperplasia epiteliale ghiandolare (adenosi) e dilatazione dei dotti per occlusione degli stessi da parte di detriti ivi depositatosi e/o per la costrizione esercitata sul lume duttale dalle aree di fibrosi periduttale e peritubulare
TERAPIA:
1. EXPECTANT MANAGEMENT: la estrema diffusione della mastopatia fibro-cistica e la fisiologica presenza di piccoli noduli mammari in pazienti sane fa ritenere l’attesa e il follow-up a medio e lungo termine la terapia di prima scelta per la maggior parte delle pazienti con mastopatia f.c.
2. TERAPIA CHIRURGICA: nelle p/ti con cisti complex o di diametro >3 cm ci si orienta verso l’exeresi chirurgica dopo agoaspirazione e/o agobiopsia. E’ consigliabile asportare la cisti se il liquido è nettamente emorragico, se dopo l’aspirazione persiste una neoformazione nodulare, se l’esame citologico mostra delle atipie e se il reperto mammografico dopo l’aspirazione è sospetto.
3. TERAPIA MEDICA:
a) progestinici o progesterone, medrossiprogesterone acetato[1] (MAP) somministrato alla dose di 10 mg al giorno a partire dal 15° giorno per 10 giorni e nei casi più gravi dal 10° giorno per 15 giorni per un periodo di 12-48 mesi. Effetti collaterali dei progestinici: blocco gonadotropinico; eventuale caduta dell’attività estrogenica con conseguenze sulla mineralizzazione ossea e sul trofismo genitale; incremento ponderale modesto ma poco tollerato dalle pazienti; un certo grado di iperandrogenismo con acne seborrea ed ipertricosi
b) E-P: buoni risultati l’utilizzazione di pillole contraccettive con una componente di etinilestradiolo molto bassa (0,02 mg) 
associata al noretindrone (1 mg).
associata al noretindrone (1 mg). c) FANS, antinfiammatori non steroidei: nimesulide, ipuprofene, ketoralac, diclofenac, piroxicam, naprossene.
d) antinfiammatori locali (flavonil© gel, associazione di ananas, rutina e bromelina): diminuiscono l’edema mammario e relativa tensione e non presentano effetti collaterali e nessun rischio per la paziente.
e) progesterone al 5% in gel o crema base in casi di mastalgia può alleviare il senso di fastidiosa tensione mammaria.
f) Danazolo (17-alfa etinil-testosterone[2]): induce una attivazione di recettori per gli androgeni nel tessuto mammario ed endometriale, bloccando i recettori degli estrogeni e del progesterone. Non sopprime la produzione di gonadotropine ma inibisce il picco preovulatorio dell’LH e quindi l’ovulazione; è l’unico farmaco approvato ufficialmente dalla FDA per la terapia della mastalgia sintomatica. .Il dosaggio del danazolo varia a seconda della intensità della sintomatoloogia e delle alterazioni mammarie e varia dai 50 mg/die fino ai 200 mg/die per 3-6 mesi.
g) Tamoxifene: Anche questo farmaco diminuisce o blocca la risposta del tessuto mammario fibrocistico agli estrogeni. Il dosaggio è di 10 mg/die per via orale, somministrati dal 5° giorno del flusso per 20 giorni, a cicli di 3 mesi (3).
h) Letrozolo (Femara© cpr 2.5 mg): una compressa al dì per cicli di 2 mesi. Il letrozolo è un inibitore di IIIa generazione dell’aromatasi, enzima che favorisce la trasformazione di Testosterone in estradiolo e di Androstenedione in Estrone.
i) LH-RH-analoghi: in caso di fallimento degli altri presidi terapeutici, come estrema ratio terapeutica a causa dei gravi effetti collaterali come irsutismo, alopecia, diminuzione del volume mammario, obesità di tipo androgeno, ittero colostatico, hot flash, secchezza vaginale ed alterazioni del flusso mestruale. Nelle p/ti >40 anni, se la tolleranza è buona e non si presentano spotting intermestruali, si ha scomparsa del dolore e della tensione mammaria e la diminuzione delle nodosità cistiche nel 70% dei casi.
l) bromocriptina (Parlodel© cpr 5-10 mg) 5 mg al giorno o cabergolina 0.25 mg (Dostinex© ½ cpr) due volte a settimana per 3-6 mesi. Il rationale di tale terapia è basato sul riscontro di elevate poussèes di prolattina nelle p/te con mastopatia f.c. e nel riscontro di alti livelli di prolattina nel liquido aspirato dalle cisti mammarie. Gli antiprolattinemici inducono una regressione numerica e funzionale dei recettori estrogenici della mammella e stimolano la secrezione ovarica di progesterone.
m) diuretici: possono, eliminando l’edema, ridurre la tensione mammaria e il dolore.
n) dieta povera di grassi
o) abolizione di bevande ricche di xantine come caffè, tè e cacao. Le xantine inibiscono l’azione della cAMP (adenosinmonofosfato ciclico) e della cGMP (guanosinadenofosfato ciclico) fosfodiesterasi.
p) Vitamine del complesso B: accelerano il catabolismo epatico degli estrogeni a livello epatico.
r) vitamina E (400-600 UI al giorno): nelle p/ti dismetaboliche con bassi livelli di lipoprtoteine sieriche ad alta densità
s) Agopuntura
[1] Depoprovera fiale 50 mg,150 mg, 500 mg e 1000 mg; Provera G cpr 5 e 10 mg; Farlutal cpr 10 mg
[2] danazol
[3] Nolvadex cpr 10 e 20 mg
Dr. Tatjana Volpicelli
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