Fattori prognostici nel melanoma e refertazione

Fattori prognostici Fattori prognostici nel melanoma e nel melanoma e refertazionerefertazione

Anatomia Patologica e Citopatologia Casa di Cura S. Pio X e Istituto Clinico S. Ambrogio, Gruppo S. Donato Anatomia Patologica e Citopatologia Casa di Cura S. Pio X e Istituto Clinico S. Ambrogio, Gruppo S. Donato - Milano- Milano

StagingStagingStaging is important to clinicians and researchers because it provides:

– a nomenclature of consistent terms and definitions based on prognosis;

– compartmentalization of patients into definable risk groups with regard to metastatic risk and survival rates;

– criteria for stratification and reporting results of clinical trials;

– a critical component for comparisons of treatment results among different centers;

– a valuable tool for clinical decision making.


Balch CM et al. CA Cancer J Clin 2004; 54:131-149

Staging system for melanomaStaging system for melanoma• Published by AJCC in 2001*• Approved by

– Union International Contre le Cancer (UICC)– World Health Organization (WHO)– European Organisation for Research and

Treatment of Cancer (EORTC)

• 17.600 patients at 13 cancer centers• Tumor (T), node (N) and metastasis (M)


*Balch CM, Buzaid AC, Soong SJ et al. Final version of the American Joint Committee on Cancer staging for cutaneous melanoma. J Clin Oncol 2001;19:3635-3648

TNM classificationTNM classification


* Micrometastases are diagnosed after sentinel or elective lymphadenectomy.† Macrometastases are defined as clinically detectable nodal metastases confirmed by therapeuticlymphadenectomy or when nodal metastasis exhibits gross extracapsular extension.‡ LDH Lactate dehydrogenase.

2002

Follow-up data of 17.600 melanoma Follow-up data of 17.600 melanoma patients according to stagepatients according to stage



Follow-up data of 17.600 melanoma Follow-up data of 17.600 melanoma patients according to nodal statuspatients according to nodal status



American Joint Committee of Cancer (AJCC) American Joint Committee of Cancer (AJCC) melanoma staging: summary of stagesmelanoma staging: summary of stages

• Stage I: Primary melanoma only ≤ 2 mm in thickness with ulceration, or ≤ 4 mm in thickness in the absence of ulceration

• Stage II: Primary melanoma only, but more advanced than stage I

• Stage III: Melanoma with regional metastasis (satellite, in transit metastasis and/or regional lymph node metastasis) in the absence of distant metastasis

• Stage IV: Distant metastasis


Stage and survivalStage and survival


T classification: the primary tumorT classification: the primary tumor

• Maximal thickness as measured histologically following Breslow’s rules

• The presence or absence of ulceration

• In thin melanomas: the deepest microanatomical level reached by the invading melanoma, according to Clark’s rules


T classification of the primary tumor: T classification of the primary tumor: thicknessthickness


T classification of the primary tumor: T classification of the primary tumor: thicknessthickness

• From the top of the granular layer to deepest invasive tumor cells / microsatellite

• Epidermal hyperplasia / extension to adnexa• Thickness in tenths of a millimeter (e.g. 0.7 mm)• Tangential sections / Frozen sections• Exophytic or endophytic growth pattern• Thin melanoma cannot be equated with early

melanoma• Regression


T classification of the primary tumor: T classification of the primary tumor: ulcerationulceration


T classification of the primary tumor: T classification of the primary tumor: ulcerationulceration

• On histological investigation

• Absence of intact epidermis overlying “a maior portion” of the melanoma (diameter)

• Artifactual or traumatic disruption of the epidermis (d.d.)

• Underestimation of the thickness

• Biologic significance


T classification of the primary tumor: T classification of the primary tumor: level of invasionlevel of invasion

• Level I – melanoma in situ

• Level II – invasion of papillary dermis

• Level III – filling of the papillary dermis by tumor

• Level IV – invasion “well into” the reticula dermis

• Level V – invasion of the subcutaneous tissues


T classification of the primary tumor: T classification of the primary tumor: level of invasionlevel of invasion

• Distinction not always straightforward

• II/III and III/IV observer variability

• Border between papillary and reticular dermis is indistinct or absent in some sites

• Fibrosis

• Invasion of reticular dermis without filling papillary dermis

• For each levels differences in thickness


T classification of the primary tumor


S-100

T classification of the primary tumor: T classification of the primary tumor: Ki67Ki67


• Gimotty, P.A., et al. Thin Primary Cutaneous Melanoma…. J Clin Oncol, 2004

• Gimotty, P.A., et al. Biologic and Prognostic Significance of Ki67…. J. Clin. Oncol. 2005

T classification of the primary tumor:mitotic index

Kesmodel, S.B. et al. Mitotic Rate as a Predictor in … Thin Melanomas. Ann. Surg. Oncol. 2005

0.3 mm


T classification of the primary tumor: T classification of the primary tumor: TIL (brisk/non brisk/absent)TIL (brisk/non brisk/absent)


T classification of the primary tumor: TIL (brisk/non brisk/absent)


0

20

40

60

80

100

0 12 24 36 48 60 72 84 96 108 120

months

% o

ve

rall

su

rviv

al

Brisk Non-brisk Absent

Clemente C et al. Cancer 1996; 77: 1303-10

Thickness (TIL) 0,0001

TIL (thickness) 0,03*Adjustments in parentheses

HGP - VGP


Tumor type BRAF Melanoma RGP 1/9 VGP 8/8

Metastases 10/10

La Porta CA, Cardano R, Facchetti F, Presicce P, Rao S, Privitera E, Clemente C, Mihm MC Jr. BRAF V599E mutation occurs in Spitz and Reed naevi. J Eur Acad Dermatol Venereol. 2006 20(9):1164-5.

G T/A G

G T G

G T/A G


Melanoma in regressione

TNM: linfonodi regionaliTNM: linfonodi regionali

pNx Lo stato dei linfonodi non può essere determinato

pN0 Non evidenza di metastasi ai linfonodi regionali

pN1Localizzazione in 1

linfonodo regionale

a. micrometastasi

b. macrometastasi

pN2

Localizzazione in 2-3 linfonodi regionali

a. micrometastasi

b. macrometastasi

c. metastasi in transit e/o satellitosi senza linfonodi metastatici

pN3 Localizzazione in 4 o più linfonodi regionali o pacchetto

linfonodale o satellitosi/metastasi in transit o melanoma ulcerato

e linfonodi/i metastatico/i


N classification: regional metastasisN classification: regional metastasis

• Regional lymph node metastases– Micrometastases - tiny lymph node metastases that

can only be detected by microscopic evaluation. – Macrometastases – clinically apparent

• Microsatellites• Satellites• In-transit metastases


Classificazione morfologica

Da: D.J. DEWAR ET AL. JCO. 22; 3345-3349, 2004

S - classificazione

S - I <0.30

S - II 0.31 - 1mm

S - III > 1mm

S = distanza dal margine interno della capsula

DA. STARZ ET AL. SEMINARS IN ONCOLOGY 31: 357-361, 2004

C. Clemente Anatomia Patologica e CitopatologiaC. Clemente Anatomia Patologica e Citopatologia

Metastasi linfonodaliMetastasi linfonodaliTipo metastasi Cellule tumorali isolate Metastasi: diametro massimo …………. mmMicrostadiazione secondo Starz SO (assenza di cellule tumorali) SI (d ≤ 0,3 mm) SII (d > 0,3mm - 1 mm) SIII (d > 1 mm)Localizzazione microanatomica Sottocapsulare secondo Dewar e Coll. Combinata Parenchimale Multifocale Estesa (diametro > 5 mm e/o estensione extracapsulare)


Overall survival at 60 months of 160 patients with positive sentinel nodes

Characteristic of patients p

Number of metastatic nodes(1,2,3,4 nodes) 0.0561

Number of deposits(1,2,3,>3 foci) 0.6634

Largest diameter of metastatic foci(single cells, <0.5,0.5-0.9,1-1.9,≥2 mm) 0.1303

Localization of metastatic foci(parenchimal sinus only, subcapsular sinus, intraparenchimal with or without subcapsular sinus)

0.1265

Extracapsular invasion(present, absent) 0.3102

Cascinelli N., et al. 2006


Un linfonodo sentinella è considerato positivo quando si

trova almeno una cellula di melanoma?


Patients with ITC in SNs have a significantly higher risk of melanoma-specific death than those with tumor-negative SNs. The 12% incidence of nonsentinel node metastasis is similar to rates reported for patients with more extensive SN involvement. Patients with ITC should be considered for CLND. (Scheri RP, Essner R, Turner RR, Ye X, Morton DL. : Ann Surg Oncol. 2007 Oct;14(10):2861).

N classification of regional metastasis:microsatellites


• Nest(s) of malignant melanocytes, >0.05 mm. in diameter in reticular dermis ,

• Present in panniculus or vessels beneath the tumor mass but separated from it by normal tissue in the section in which the Breslow measurement made

• Microsatellites should be included in the thickness measurement

Leon, P. Daly J.M. Synnestvedt, M. et al. The prognostic implications of microscopic satellites in patients with clinical stage I melanoma. Arch surg 126; 1461-1468, 1991

Fattori prognostici morfologici nel melanoma primitivo: invasione vascolare

• 35.3% di sopravvivenza a 8 a. vs. 73.9%

• Ripresa di malattia a 10.2 mesi vs. 26.1 mesi (p<.001)

• Sopravvivenza globale 32.6 mesi vs. 54.2 mesi (p=.001)

• L’effetto sfavorevole sulla prognosi si mantiene anche in analisi multivariate


Kashani-Sabet M, Sagebiel RW, Ferreira CM, Nosrati M, Miller JR 3rd. Vascular involvement in the prognosis of primary cutaneous melanoma. Arch Dermatol 137; 1169-1173, 2001

Fattori prognostici morfologici nel melanoma primitivo: invasione neurale

• Riduzione, statisticamente significativa, della sopravvivenza nel melanoma desmoplastico

• Riduzione della sopravvivenza anche in altri tipi di melanomi

• Aumentata frequenza di recidive locali


Baer SC, Schultz D, Synnestvedt M, Elder DE. Desmoplasia and neurotropism. Prognostic variables in patients with stage I melanoma.Cancer. 1995 Dec 1;76(11):2242-7.

N classification of regional metastasis:satellites


Ten year survival: With satellites 37%Without satellites 65%

•Leon P, Daley JM, Synnetvedt M, et al. The prognostic Implications of microscopic satellites in patients with Clinical stage One melanoma. Arch of Surgery. 126(12)1461-8.1991

•Harrist TJ, Rigel DS, Day CL Jr. et al: Microscopic satellites” are more highly associated with regional lymph node metastases than is primary melanoma thickness. Cancer. 53 (10)2183-7. 1984

N classification of regional metastasis:in transit metastases


Differences Between the Previous Version (1997) and the Present Version (2002) of the Melanoma Staging System


M classification: distant metastasisM classification: distant metastasis

• Any T any N M1a

• Any T any N M1b

• Any T any N M1c

• Distant skin, subcutaneous, or nodal mets with normal LDH levels

• Lung mets with normal LDH

• All other visceral mets with normal LDH or any distant mets with elevated LDH


Anatomia Patologica e Citopatologia Casa di Cura S. Pio X e Istituto Clinico S. Ambrogio, Gruppo S. Donato Anatomia Patologica e Citopatologia Casa di Cura S. Pio X e Istituto Clinico S. Ambrogio, Gruppo S. Donato

- Milano- Milano

Survival curves of 1,158 patients with metastatic melanomas at distant sites subgrouped into three categoriesor sites: skin, subcutaneous tissue, or distant lymph nodes versus lung versus all other visceral sites.


Fattori prognostici morfologici nelle metastasi a distanza (IV stadio)

• Sopravvivenza media a 6-7 mesi• Sopravvivenza a 5 anni 6-7%• Variabili:

– Numero delle sedi metastatiche– Sede viscerale / non viscerale– Intervallo libero e stadio prima della metastasi a

distanza– Resecabilità della localizzazione (unica)– Dimensione della metastasi


Differences Between the Previous Version (1997) and the Present Version (2002) of the Melanoma Staging System


Biomarcatori del melanoma

• Chromosomal / DNA content markers• Cell-cycle markers / regulators• Anti-apoptosis / apoptosis markers• Nuclear proteins and transcription factors• Receptor tyrosine kinases• Cell adhesion and motility molecules• Extracellular degrading/proteolytic enzymes• Immunoregulators/immune markers• Angiogenesis and other growth factors• Expression profiling technique for gene identification


Refertazione1. Istotipo (SSM,NM,LMM, ALM,MLM, ecc.)

a. Fase orizzontale (fase verticale)

2. Ulcerazione (valutazione microscopica)

3. Livello: I (melanoma in situ/melanosi pre-maligna), II, III, IV

4. Spessore: .. mm (è sufficiente un decimale)

5. Infiltrati linfocitico intratumorale (TIL): brisk/non brisk/assente

6. Infiltrato linfocitico peritumorale (opzionale)

7. Mitosi per mm2 (<1, tra 1 e 6, > 6)

8. Regressione

a. Spessore dell’area di regressione se superiore allo spessore del melanoma

9. Invasione vascolare

10. Invasione peri-neurale

11. Satellitosi microscopica

12. Margini di resezione (distanza macroscopica)

13. Nevo associato

14. pTNM


Fattori prognostici nel melanoma e refertazione

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