MELANOMA Risk factors Intermittent exposure to ultraviolet radiation Endogenous factors (skin type) Critical time (childhood)

Transcript

1 MELANOMA Risk factors Intermittent exposure to ultraviolet radiation Endogenous factors (skin type) Critical time (childhood)

2 MELANOMA Risk factors Exposure to UV (intermittent) Endogenous factors (skin type) Sunburns during childhood

3 Epithelium associated Melanoma High UV Low UV Glabrous Mucosal CSD Desmopl Non-CSD Spitzoid Acral Mucosal > ys 50ys <40ys > 50-60ys

4 MELANOMA Risk Factors Family history : 6-14% of melanoma cases (Tucker et al, 1997) Precursor lesions : 5.7% cumulative risk in large congenital nevi (Egan, 1998) >100 common nevi >6 dysplastic nevi (Ang, 1998)

5 MELANOMA Risk Factors Gene alteration: CDKN2 ( p16 and P19arf) cell-cycle inhibitory gene mapped to chromosome 9p21 Mutation are reported in familial and sporadic melanoma (no diagnostic or prognostic relevance till now) (Goldstein and Tucker J, NCI 1997) CDK4 cell-cycle deregulation

6 Classificazione Istologica Cancer 1973 Dec;32(6): The classification of malignant melanoma and its histologic reporting. McGovern VJ, Mihm MC Jr, Bailly C, Booth JC, Clark WH Jr, Cochran AJ, Hardy EG, Hicks JD, Levene A, Lewis MG, Little JH, Milton GW. Sidney,1972

7 Classificazione Istologica Recommended Terminology AJCC VII Ed Superficial Spreading Lentigo Maligna Acral Lentiginous Mucosal Lentiginous Nodular Unclassifiable Others: Melanocitoma, MM in blue nevus, Meningeal, ocular

8 Superficial Spreading Type

9 Lentigo Maligna Type

10 Acral Lentiginous Type

11 Mucosal Lentiginous Type

12 Nodular Type

13 Classificazione Istologica (Istotipo) valore prognostico scarso espressione di etiopatogenesi (LM esposizione continua ad UV SS esposizione intermittente ad UV) espressione di un diverso comportamento biologico (aggressività: ALM >SS > LM) non identifica gruppi potenzialmente sensibili a strategie terapeutiche

14 Classificazione molecolare Identificate numerose alterazioni molecolari (mutazioni) a carico di geni implicati nella regolazione dei processi di proliferazione e differenziazione cellulare (BRAF, NRAS, HRAS, ckit, GNAQ, GNA11) Alcune rappresentano un target terapeutico Non hanno valenza diagnostica ne correlano con l istotipo

15 Epithelium associated Melanoma High UV Low UV Glabrous Mucosal CSD Non-CSD Spitzoid Acral Mucosal BRAF NRAS Fusion /- - HRAS /- - KIT

16 Non-epithelium associated Melanoma Eye Internal organs Dermal Uveal Meningeal M in BlueN M in CN NRAS GNAQ GNA

17 Referto Istopatologico Esame Macroscopico Esame Microscopico

18 Esame Macroscopico Descrizione del Prelievo numero dimensioni tipo di fissativo Descrizione della/le lesione/i forma bordi colore dimensioni ulcerazione distanza dai margini

19 Scheda istopatologica

22 I principali fattori prognostici del melanoma che definiscono il T AJCC/TNM VII Ed Spessore di Breslow (misurato in mm) Ulcerazione (determinata istologicamente) Mitosi/mmq

23 Spessore secondo Breslow: il principale fattore prognostico Ann Surg Nov;172(5): Thickness, cross-sectional areas and depth of invasion in the prognosis of cutaneous melanoma. Breslow A. Pathol Annu. 1980;15(Pt 1):1-22. Prognosis in cutaneous melanoma: tumor thickness as a guide to treatment. Breslow A.

24 Spessore secondo Breslow McGovern VJ et al.,pathology 1986, 18:12-21

25 Balch CM et al., Semin. Surg. Oncol. 21:43-52 Fig 3. Observed and predicted 10-year mortality rate of 15,320 patients with clinically localized melanoma based on a mathematical model f(t) = e (-211t+0.009t2) derived from the AJCC melanoma database. T is the measured tumor thickness (mm) and f(t) is 10-year melanoma-specific mortality rates. P <.0001.

26 Ulcerazione The absence of an intact epidermis overlying a major portion of the primary melanoma based on microscopic examination of the histologic sections McGovern VJ et al.:histopathology 6: ,1982 Balch CM et al:j Clin Oncol 19: ,2001

27 AJCC TNM Staging System Categories: T Ulceration for defining subcategories of T a: without ulceration b: with ulceration

28 Balch CM et al., Semin. Surg. Oncol. 21:43-52 Fig 2. Ten-year survival rates comparing the different T categories and the stage groupings for stages I and II melanoma. Note that the groupings upstage patients with melanoma ulceration with the next level T substage of patients with thicker, nonulcerated melanomas.

29 Mitotic Rate Proliferation of the primary melanoma as defined by the mitotic rate was identified as a powerful and independent predictor of survival. Multiple thresholds of mitotic rate were examined statistically, and the most significant correlation with survival was identified at a threshold of at least 1/mm 2. Balch CM, Gershenwald JE, Soong SJ, et al: Final version of 2009 AJCC melanoma staging and classification. 27: , J Clin Oncol

30 AJCC TNM Staging System Categories: T Mitotic rate - Find the dermal area with most mitotic figures - Count mitotic figures in this so called hot spot area - Extend counting in adjacent fields covering 1 mm² area 1 mm²

31 Mitosi Hum Pathol Dec;32(12): High proliferative activity may predict early metastasis of thin melanomas. Frahm SO, Schubert C, Parwaresch R,RudolphP. Department of Pathology, University of Kiel,Germany

32 Livello di Invasione secondo Clark Mc Govern VJ et al.,cancer 1973,32:

33 Livello di Invasione secondo Clark: un fattore prognostico da dimenticare? SI Oggetto di critiche declassato come fattore prognostico scarsa riproducibilità tra patologi soppiantato dall indice mitotico anche nei melanomi < 1 mm

34 I principali fattori prognostici del melanoma che definiscono il T AJCC/TNM VII Ed. Spessore di Breslow (misurato in mm) Ulcerazione (determinata istologicamente) Mitosi/mmq

35 AJCC /TNM Staging System VII Ed: T pt is Melanoma in situ

36 AJCC TNM Staging System Categories: T pt1 thickness < 1mm 0,75 mm

37 AJCC TNM Staging System Categories: T pt1a : < 1mm no ulceration; no mitoses mitosis pt1b : < 1mm Ulcerated or at least 1 mitosis

38 Fase di Crescita Melanoma in Fase di Crescita Radiale (RGP) -Melanoma in situ (intraepiteliale) -Melanoma microinvasivo Melanoma in Fase di Crescita Verticale (VGP)

39 Fase di crescita Radiale

40 Fase di crescita Verticale For a melanoma to acquire competence for metastasis it must progress to the next step of tumor progression the vertical growth phase. This lesional step is characterized by the appearance of a new population of cells within the melanoma, not an expansion of the cells forming the pre-existing radial growth phase. The net growth of the cells of the vertical growth phase is perpendicular to the directional growth of the radial growth phase Hum Pathol Dec;15(12): Clark WH jr et al,

41 Fase di crescita Verticale

42 Elder D.E. and Murphy G.F. Melanocytic Tumors of the Skin Atlas of Tumor Pathology-AFIP-1991 VGP Melanoma /Tumorigenic Melanoma Dermal component: - one or more nests of cells morphologically different from the intraepidermal ones - clusters larger than the largest intraepidermal nests* - mitoses * - level III or IV or V - clusters with growth advantage over adjacent tissue * Melanoma with these features are tumorigenic by definition

43 Ann Surg Oncol May;7(4): Bedrosian I et al. METHODS: Among 235 patients with clinically localized cutaneous melanomas who underwent successful SLN biopsy, 71 had lesions 1 mm or smaller with a VGP...RESULTS: The rate of occurrence of SLN metastasis was 15.2% in patients with melanomas deeper than 1 mm and 5.6% in patients with thin melanomas...conclusions: VGP in a melanoma 1 mm or smaller seems to be a risk factor for nodal metastasis. The risk of nodal disease may not be accurately predicted by the use of a multivariate logistic regression model that incorporates thickness, mitotic rate, regression, tumor-infiltrating lymphocytes, sex, and anatomical site. Patients with thin lesions having VGP should be evaluated for SLN biopsy and trials of adjuvant therapy

44 Infiltrato linfocitico Tumorale TIL - Presenza di linfociti all interno della VGP - Rappresenta una risposta dell ospite (T-linfociti) - Linfociti circondano a rosetta singole cellule - Tre categorie: Absent, Non Brisk, Brisk

45 Cancer Apr 1;77(7): Prognostic value of tumor infiltrating lymphocytes in the vertical growth phase of primary cutaneous melanoma. Clemente CG, Mihm MC Jr, Bufalino R, Zurrida S, Collini P, Cascinelli N. BACKGROUND:...we reviewed 285 consecutive cases of primary cutaneous melanomas (American Joint Committee on Cancer Stage I and II). RESULTS. The 5- and 10-year survival rates for melanoma with a vertical growth phase and a brisk infiltrate were 77% and 55%, respectively. For tumors with a nonbrisk infiltrate, the 5- and 10-year survival rates were 53% and 45%, respectively, and for tumors with absent tumor infiltrating lymphocytes, the 5- and 10-year survival rates were 37% and 27%, respectively.

46 Infiltrato linfocitico Tumorale TIL

47 Regressione - Fenomeno spontaneo immunomediato - Interessa più spesso il melanoma in RGP - Alcuni autori riconoscono diversi stadi - Significato prognostico controverso

48 Regressione

49 Effetto della Regressione sulla Prognosi nel melanoma sottile Autore N. pazienti Regression e % Metastasi Regressione (No Regres) Effetto sulla prognosi Gromet, (2) % Avverso Trau, (0) Nullo McGovern, (5) Nullo Kelly, (3.8) Nullo Sondergaard, Avverso Naruns, Avverso Shaw, (6,1) Nullo Slingluff, (17) Avverso Blessing, Avverso

50 Linfonodo Sentinella

51 AJCC TNM Staging Categories: N N1 and N2 a: micrometastasis Detected only by pathological examination of SLNB; no lower threshold of dimension N1 and N2 b: macrometastasis Clinically detected and confirmed by pathological examination after CLND only N2 c: microsatellite/in transit mts without metastatic node

52 Scheda Linfonodo Sentinella

53 Scheda Linfonodo Sentinella

54 AJCC TNM Staging Categories: N Rotterdam Dewar Combined (RDC) criteria < 0,1 mm /subcapsular > 0,1 mm / not subcapsular OS 5ys :91% NSN positivity rate 5,5% bad prognosis Van der Ploeg JCO 2011;29:

55 AJCC TNM Staging Categories: N Rotterdam Dewar Combined (RDC) criteria The strongest predictive parameter for NonSLN positivity and melanoma specific survival Van der Ploeg JCO 2011;29:

56 Cosa chiedere al Patologo Diagnosi Stadiazione adeguata (fattori prognostici) Idonea selezione del materiale per indagini molecolari (lesione piu recente, quantita adeguata di tumore vitale, eterogeneita delle aree tumorali da esaminare) Linfonodo sentinella (campionamento, IHC, dimensioni e sede di micrometastasi)