Tumore di Spitz atipico

IL MELANOMA
Claudio Clemente
Servizio di Anatomia Patologica e Citopatologia
Casa di Cura San Pio X
IRCCS Policlinico San Donato
MILANO
Il melanoma scrive il suo
messaggio sulla cute perché tutti
possano vederlo. Ma gli occhi non
possono vedere quello che la
mente non conosce, così alcuni
vedono ciò che è scritto ma non
comprendono il messaggio. Quelli
che comprendono il messaggio
salveranno molte vite agendo in
modo appropriato
Neville Davis, Brisbane, Queensland , Ann Plast Surg
1978 Nov; 1(6): 628-9
In a 1960s examination of nine
Peruvian Inca mummies, radiocarbon
dated to be approximately 2400 years
old, which showed apparent signs of
melanoma: melanotic masses in the
skin and diffuse metastases to the
bones (skull, long bones, scapula).
O.Urteaga, G.T.Pack.
On the antiquity of melanoma.
Cancer 1966;19:607-610
John Hunter is reported to be the first to
operate on metastatic melanoma.
Although not knowing precisely what it
was, he described it as a "cancerous
fungous excrescence".
1787
Specimen in the Hunterian Museum of secondary melanoma excised by John
Hunter. JP Bennett and P All. Moles and melanoma: a history. Ann R Coll Surg Engl
1994; 76: 373
1804
The French physician René
Laennec was the first to
describe melanoma as a
disease entity.
His report was initially
presented during a lecture
and then published as a
bulletin in the journal of the
Faculté de Médecine de
Paris
1857
The first English language report
of melanoma was presented by
an English general practitioner
from Stourbridge, William Norris
in 1820. In his later work in 1857
he remarked that there is a
familial predisposition for
development of melanoma
(''Eight Cases of Melanosis with
Pathological and Therapeutical
Remarks on That Disease'').
1840
The
first
formal
acknowledgment
of
advanced melanoma as
untreatable came from
Samuel Cooper. He stated
that the only chance for
benefit depends upon the
early removal of the
disease.
First lines of theory and practice of
surgery. Longman, Orme, Brown, Green
and Longman.
Herbert Snow (1847–1930), a London
surgeon with a particular interest in
melanoma, was a controversial proponent
of anticipatory gland excision well before
acceptance of elective lymph node
dissections.
In 1907, Sampson Handley proposed that
melanoma should be removed with a 2inch margin of normal skin, measured in
all directions around the cancer.
1907
1957
Lewis CW: lecture given to the Dermatological Association of Australia at the Royal Perth
Hospital on 15th October, 1957
1956
Australian professor Henry
Oliver Lancaster discovered
that melanomas were
directly associated with
latitude (ie, intensity of
sunlight) and that exposure
to the sun was a very high
factor in the development
of the cancer
Campagne di prevenzione
Da molti anni sono state pianificate
campagne di educazione sanitaria che
hanno fatto registrare un aumento del
numero di melanomi diagnosticati in
fase precoce, a prognosi favorevole e
con una documentata riduzione di
mortalità rispetto alle aree in cui non
sono state mai organizzate campagne
educazionali, tuttavia l’analisi dei dati a
lungo termine non ha confermato
questo trend.
Il melanoma ieri e il melanoma oggi …
< 50mm >
< 1970
< 25mm >
< 10mm >
<3mm>
2012
Lo spessore medio del melanoma è diminuito da 1.81 mm nel 1976 a 0.53 mm nel 2000 (P < 0.0001)
Buettner PG, Leiter U, Eigentler TK, Garbe C. Development of prognostic factors and survival in cutaneous melanoma over 25 years: An analysis of the Central Malignant
Melanoma Registry of the German Dermatological Society. Cancer. 2005 Feb 1;103(3):616-24.
Cox regression analysis for 13,581 melanoma patients
without evidence of nodal or distant metastases
Prognostic Factors Analysis of 17,600 Melanoma Patients: Validation of the American Joint
Committee on Cancer Melanoma Staging System. Charles M. Balch et al. J Clin Oncol, 19:3622-3634
AJCC CANCER STAGING MANUAL
Seventh Edition, October 2009
Nevo di Spitz
Sophie Spitz 1910-1956
• In 1948 Sophie Spitz described a nevus
in children that could be confused with
melanoma.
• This entity, the spindle and epithelioid
cell nevus, was called « benign juvenile
melanoma», a poor term because
benign melanoma is an oxymoron and
Spitz nevus may also occur in adults
• The name of Spitz nevus was first used
by McGovern (1967)
• Spitz and Allen were the first to
recognize the importance of ulceration
as a major adverse prognostic factor
BRAF MUTATION IN Spitz/Reed nevi
FOR
REV
SPITZ NEVUS
FOR
REV
G T/A G
G T/A G
ATYPICAL SPITZ TUMOR
C A/T C
C A/T C
1
1
G T/A G
G G/A A
C A/T C
c c A/G
2
2
G T/A G
G1978A
C A/T C
FOR
3
REV
REED NEVUS
G T/A G
G T/A G
C A/T C
C A/T C
1
4
G
G
T/A
G
G
T/A
C A/T C
G T/A G
C A/T C
2
5
G T/A G
C A/T C
C A/T C
3
6
T1976A
T1976A
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.
1999
Tumore di Spitz atipico: grading
• Età superiore a 10 anni (1 punto)
• Tumore di diametro > 10 mm (1punto)
• Estensione al tessuto adiposo, ulcerazione o
mitosi da 6 a 8 per mm2 (2 punti per ciascuno)
• Mitosi superiori 8 per mm2 (5 punti)
--------------------------------------------------------------0-2 punti: basso rischio
3-4 punti: rischio intermedio
5-11 punti: rischio elevato
Spatz A. et al Spitz tumors in children: a grading system for risk stratification. Arch Dermatol 1999; 135:282
• tre campi istologicamente identificati sull’H&E e 30-60 nuclei non sovrapposti
• due esperti nella lettura FISH, senza conoscere la interpretazione istopatologica
Analisi con FISH interfasica (4 sonde Vysis/Abbott) utilizzando il cut off
secondo Gerami (2009) in 141 neoplasie melanocitiche spitzoidi
Clemente C. Risultati presentati al 5°Congresso Italiano di Anatomia Patologica,
Bologna, 21-25 settembre 2010
2010
State of the art, nomenclature, and points of consensus and controversy concerning
benign melanocytic lesions: outcome of an international workshop. Barnhill RL, Cerroni
L, Cook M, Elder DE, Kerl H, LeBoit PE, McCarthy SW, Mihm MC, Mooi WJ, Piepkorn MW,
Prieto VG, Scolyer RA. Adv Anat Pathol. 2010 Mar;17(2):73-90.
Areas of controversy:
- including nevi with halo reactions, traumatized nevi,
"dysplastic" nevi, and nevi from particular anatomic sites;
- malignant transformation associated with congenital nevi;
- atypical spitzoid neoplasms;
- particular melanocytic cellular phenotypes
- blue nevi, combined nevi, and other controversial lesions such
as deep penetrating nevus and pigmented epithelioid
melanocytoma.
The Group recommended the description of ambiguous or
"borderline" lesions as tumors with indeterminate or
uncertain biologic/malignant potential.
ASN
AST
B-DPN
BMT
BNM
FAMMM
MANIAC
MelTUMP
PEM
pASNT
SNAFs
SPARK’s nevi
Atypical Spitz nevus
Atypical Spitz Tumor
Bordreline melanocytic proliferation arising in
association with a deep penetrating nevus
Borderline Melanocytic Tumor
Nevoid BMT
Familial atypical multiple mole melanoma
Melanocytic acral nevus with intraepidermal ascent
of cells
Melanocytic Tumors of Uncertain Malignant Potential
Pigmented epithelioid melanocytoma
Pediatric Atypical Spitz nevus/tumors
Spitz nevi with Atypical Features
Nevi with cytologic characteristic of Spitz and
architectural features of Clark’s/dysplastic nevus
Proposta di classificazione dei tumori melanocitici
(Clemente C., Mihm C. Martin Jr. 2012)
Nevi:
Lentigo simplex
Nevo giunzionale, composto e dermico
Nevo congenito
Nodulo di proliferazione in nevo congenito
Nevo alonato
Nevo dei genitali
Nevo ricorrente
Nevo pigmentato a cellule fusate (nevo di Reed)
Nevo a cellule epitelioidi e fusate (nevo di Spitz)
Nevi, varianti rare
Nevo displastico
Displasia melanocitica intraepiteliale epitelioide
Tumori melanocitici atipici (borderline)
Tumore di Reed atipico
Tumore di Spitz atipico
Tumori melanocitici atipici, varianti rare
Melanoma
Melanosi premaligna (melanoma in situ)
Lentigo maligna
Melanoma a diffusione superficiale
Melanoma tipo lentigo maligna
Melanoma acrale lentigginoso
Melanoma mucoso lentigginoso
Melanoma nodulare
Melanoma, varianti rare
Melanoma in nevo congenito
Melanoma nevoide
Melanoma a deviazione minima
Melanoma spitzoide
Altre varianti rare
Melanocitosi dermiche:
Nevo blu
Nevo blu cellulato
Nevo desmoplastico
Nevo penetrante profondo
Melanocitosi dermiche atipiche (borderline)
Nevo blu cellulato atipico
Melanocitoma epitelioide pigmentato
Tumore penetrante profondo atipico
Melanocitosi maligne
Nevo blu maligno
Melanoma desmoplastico
1969 « Clark levels of invasion»
Wallace H. Clark, Jr. 1924-1997
Wallace H. Clark Jr.
• 1966 along with Thomas B. Fitzpatric he
founded the first multidisciplinary
pigmented lesion clinic at MGH, Temple
University and University of Pennsylvania
• 1978 B-K mole syndrome and dysplastic
nevus
• Melanoma progression: radial growth phase
and vertical growth phase
Levels of invasion
• Included in the AJCC Clinical Staging
only in the PT1 category of tumors
1mm or less in thickness
(pT1b for level IV or V)
• Nevertheless, most clinicians expect
level of invasion to be included in the
report.
Dysplastic nevus
Hum Pathol 22:313, 1991
Melanoma progression
1972 « Classification and reporting of melanomas»
Vincent J. McGovern 1915-1983
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. Cancer. 1973 Dec;32(6):1446-57.
Activated oncogenic pathways important in melanoma
Scolyer RA et al. Evolving concepts in melanoma classification and their relevance to
multidisciplinary melanoma patient care. Molecular Oncology 2011, 5: 124-136
Melanoma molecular classification
Melanomas arising from mucosal, acral, chronically sundamaged surfaces sometimes have oncogenic mutations in KIT
Some uveal melanomas have activating mutations in GNAQ and
GNA11, rendering them potentially susceptible to MEK
inhibition.
These findings suggest that prospective genotyping of patients
with melanoma should be used increasingly as we work to
develop new and effective treatments for this disease.
Treatment implications of the emerging molecular classification system for
melanoma Emanuela Romano MD a, Prof Gary K Schwartz MD a, Prof Paul B Chapman
MD a, Jedd D Wolchock MD a, Dr Richard D Carvajal MD The Lancet Oncology, Volume
12, Issue 9, Pages 913 - 922, September 2011
1970: Tumor thickness
Alexander Breslow 1928-1980
10 year mortality rate of 15,320 patients with clinically
localized melanoma based on a mathematical model f(t)
0.988e AJCC melanoma database. P < .0001.
T4
T3
T2
T1
Prognostic Factors Analysis of 17,600 Melanoma Patients: Validation of the American Joint Committee on Cancer Melanoma
Staging System. Charles M. Balch et al. J Clin Oncol, 19:3622-3634
Ulceration
• The five year survivorship
– in Stage I–II melanomas decreased from 80 to
55% in the presence of ulceration
– Stage III melanomas dropped from 53 to 12%.
• The majority of melanomas greater than
4.0 mm in thickness are ulcerated.
• When tumors had an ulcer diameter of
greater than 6.0 mm the prognosis was even
worse.
Ulceration
Mitotic rate in melanoma
• In Clark's original work on mitotic activity,
0 vs 1–6 vs >6 mitoses per square millimeter
were the break-points of analysis.
• In 3661 patients from Australia, the most
statistically powerful prognosticator of survival
after thickness.
• A mitotic rate of 1 or more per square
millimeter was associated with a significant
reduction in survivorship
• It should now be used as one defining criteria
of T1b melanomas.
Melanoma ≤ 1 mm
0.3 mm
Highly significant correlation
with increeasing mitotic rate
and declining survival rates
especially
within
thin
melanoma subgroups
Thicknesss
Mitosis
(mm)
Survival rate ± SE
5-year
10-year
N
0.01-0.50
<1
0.99
0.97
1,194
0.01-0.50
>1
0.97
0.95
327
0.51-1.00
<1
0.97
0.93
1,472
0.51-1.00
>1
0.93
0.87
1,868
Survival rates for 4861 T1 melanoma patients (1.00 mm or less)
subgrouped by thickness and mitotic rate of the primary melanoma
Tumor-Infiltrating Lymphocytes (TILs)
• A lymphocytic response to the vertical growth
phase component influences prognosis.
• The presence of TILs was shown to be a
significant prognostic factor by Clemente et al,
confirming Clark's observation from 1989
concerning the prognostic significance of TILs.
• Survival differences were highly significant,
being 77% at 8 years for patients whose tumors
showed brisk infiltration, 53% for those with
nonbrisk infiltration and 37% for those whose
tumors were designated as having absent TILs.
TIL (brisk/non brisk/absent)
% overall survival
100
80
60
40
Thickness (TIL)
0,0001
TIL (thickness)
0,03
*Adjustments in parentheses
20
Clemente Cancer 1996;77:1303
0
0
12
24
36
48
60
72
84
96
months
Brisk
Non-brisk
Absent
108 120
Regression
• Complete regression, characterized by an area of
absent melanocytic growth in the epidermis and
dermis may signify a worse prognosis.
• Not all investigators have found regression to have
a significant survival impact.
• Regression of over 75% may be the critical volume
that portends metastasis.
• One case–control study confirmed that extensive
regression was present in 42% of melanomas
<1 mm in thickness that metastasized, vs only 5% of
thin melanomas that did not.
Microscopic satellites
• Microscopic satellites (reticular dermal tumor
nodules greater than 0.05 mm in width
separated from the main vertical growth phase
component) are associated with lymph node
metastasis, and with decreased disease-free
and overall survival.
• Clark et al found a reduction of actuarial 8-year
survival from 75 to 40% when satellites were
identified
Blood vessel and lymphatic invasion
• Some studies have correlated the frequency of
angiolymphatic invasion with increasing depth and level
of tumor invasion, while others have shown vascular
invasion to be a significant predictor of metastasis or of
reduced survival.
• Recent data has shown a reduced survivorship of some
40% over 8 years when angioinvasion is demonstrated
in primary tumors in vertical growth phase.
• In modern multivariate analytic systems, angioinvasion is
equivalent in prognostic import to ulceration, and second
only to thickness, as a measure of survival probability.
1960: Sydney Melanoma Unit - database
Gerald W. Milton 1924-2007
• Founded the Sydney Melanoma Unit
(SMU) in 1960, the largest melanoma
unit in the world.
• Information of more than 27,500
patients; over 1000 publications;
• Data have formed a major part of the
International American Joint
Committee on Cancer (AJCC)
database that has been used to revise
the AJCC melanoma syaging system
• Multidisciplinary approach to
melanoma
1966: clinical diagnosis of melanoma
Thomas B. Fitzpatrick 1919-2003
• Pioneer in the early diagnosis and in
esteblishing the natural history and risk
factors for melanoma.
• In 1966, along Clark, Mihm, Raker
Fitzpatrick established tha first
multidisciplinary pigmented lesion clinic
at MGH of Boston
• In 1973 color atlas of melanoma
published in the New England Journal of
Medicine
• Melanoma Clinical Cooperative Group
(MCCG) with Clark, KopfBlois, Mihm and
Sober.
Dermatopathology
Martin C. Mihm, Jr.
EVOLUZIONE DELLA DERMOSCOPIA
1920
Saphier
1933
Hinselmann
1950
1970
Goldman
MacKie
1980
1990
2000
Fritsch & Pechlaner
Pehamberger et al.
Kreusch & Rassner
Stolz et al.
Soyer et al.
Menzies et al.
Argenziano et al.
… etc. ect.
EVOLUZIONE DELLA METODICA
E R A
1920
A N A L O G I C A
ERA DIGITALE
1990
Resection margins
• 4 to 5 cm margins of resection around a primary melanoma is
not justified.
• A prospective randomized trial by the WHO Melanoma Group
showed that for melanomas up to 2 mm thick, a 1 cm margin
provides local control similar to that observed after a 3 cm
margin.
• Another prospective randomized trial by the Melanoma
Intergroup Committee in the United States concluded that for
melanomas 1 to 4 mm in thickness, a 2 cm margin of
resection provides local control that is as good as a 4 cm
margin.
• For melanomas thicker than 4 mm, the current evidence
suggests that a 2 cm margin is adequate.
Semin. Surg. Oncol. 14:272–275, 1998. © 1998
ASPORTAZIONE DELLA LESIONE
PRIMITIVA
Sospetta o Maligna
Escissione completa a pochi mm.
dal margine per non alterare il
drenaggio linfatico
Radicalizzazione
Exeresi radicale a una distanza
compresa fra 1-2 cm. dal margine,
comprende il sottocute fino alla fascia
muscolare sottostante esclusa
1992: sentinel lymph node
Linfonodo sentinella: esame al criostato
• Nella prima descrizione del metodo, Morton utilizzò l’esame
estemporaneo intraoperatorio (Technical details of intraoperative
lymphatic mapping for early stage melanoma. Arch Surg
1992;127:392-9)
• Dal febbraio 1994, nell’ambito del WHO Melanoma Programme, è
stato attivato una studio multicentrico di fattibilità che prevedeva
l’esame estemporaneo intraoperatorio
• Nel giugno 1998 il WHO Melanoma Programme ha proposto che
negli studi clinico-patologici l’esame estemporaneo intraoperatorio
sia opzionale
• Alcuni autori (AJ Cochran, IAP 1998) raccomandano l’esame del
linfonodo sentinella solo su materiale fissato in formalina ed incluso
in paraffina
Linfonodo sentinella: linee guida
http://www.siapec.it
1,108 consecutive patients with stage IB and II melanoma were submitted to sentinel
node biopsy; 176 patients (15.9%) had occult node metastases.
1.00
0.75
N-(ns)/N+(s)
0.50
N-(ns)/N-(s)
N+(ns)/N-(s)
0.25
Probability
OS of 1108 patients according to NSN and SN status
N+(ns)/N+(s)
0.00
p < 10-5
0
12
24
36
48
885
143
47
33
72
84
112
19
8
3
140
9
7
3
96
108
120
11
4
1
1
1
Months
Patients at risk
N-(ns)/N-(s)
N-(ns)/N+(s)
N+(ns)/N-(s)
N+(ns)/N+(s)
60
671
113
39
29
547
83
28
16
400
61
19
11
N-(ns)/N- (s) vs N-(ns)/N+(s) : p =0.0004
307
49
14
8
215
32
10
6
68
5
2
2
N+(ns)/N- (s) vs N+(ns)/N+(s) : p=0.1342
Cutaneous melanoma still represents
a paradox among all solid tumors.
It is the cancer for which the best
prognostic markers ever identified in
solid tumors are available, yet there is
very little understanding of their
biological significance.
Melanoma with metastatic disease
The median survival time for
melanoma patients with metastatic
disease is 8–9 months, and the 3year overall survival (OS) rate is less
than 15% (Balch et al., 2009)
Chemotherapy
• Approved (FDA) in 1975, Dacarbazine (DTIC) has
long been the standard treatment for this
aggressive disease and offers response rates up
to about 15-20% (Lui et al., 2007).
• Complete or durable responses are rare, median
survival is not improved, and the 5-year survival
rate remains less than 2%.
• Combinations added either a vinca alkaloid or
cisplatin to dacarbazine, minimal improvement in
response rate (20% to 30%) was observed.
Biologic response modifiers 1.
• The relationship between melanoma and the
immune system has been recognized for decades.
• Interferon and interleukin-2 (IL-2) have important
roles in both adjuvant therapy and treatment of
metastatic disease.
• Single-agent interferon alfa has a response rate of
15% and complete remission rates of 3% to 5%
Biologic response modifiers 2.
• Rosenberg treated a series of metastatic
melanoma patients with a high-dose of IL-2.
A response was observed in 15% to 20% of
patients. 5% to 7% of patients achieved
complete, durable remissions of disease and
the 7-year survival rate was 10%.
• IFN-a and IL-2 treatment is associated with
intense toxicities and no clear impact on OS
(Eggermont and Schadendorf, 2009).
Key pathways and therapeutic targets in melanoma
Vemurafenib
Dacarbazine
CR
PR
0.9%
0
47.5%
5.5%
Overall
response rate
48.4%
5.5%
Antimelanoma as of December, 2010
More than 10 Drug Classes
Kinase
inhibitors
Immunomodulating
antibodies
Chemothepateutics
agents
Vaccination
MAGE A3
ipilimumab
DTIC
Anti-PD1
TMZ
Anti-CD137
FTM
Anti-CD40
CDDP
iAKT
OX40
Paclitaxel
Plasmid /
Oncolytic Virus
imTOR
Anti TGF b
NABpaclitaxel
Allovectin-B7
GSI
L19IL2
iBRAF
iMEK
ic-Kit
iPI3K
PARP
inhibitors
ABT-888
Anti-angiogenic
Agents
Immunomodulating
small molecule
Pro-apoptotic
Drugs
1 MT
HDAC
PRAME
NY-ISO1
IL2 + gp100
Onco-Vex
Adoptive Cell
therapies
ANATOMIA PATOLOGICA
Casa di Cura San Pio X - Milano
Dr. Stefania Rao
Dr. Annamaria Ferrari
Dr. Federica Cetti Serbelloni
Dr. Agostino Crupi
Dr. Luigi Mascheroni
Dr. Leonardo Lenisa
Dr. Natale Cascinelli
I.R.C.C.S. Policlinico San Donato, Milano
Dr.Barbara Rubino
Dr. Barbara Bruni
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Dr. Sara Leoncini
…. e tutto il personale tecnico e amministrativo dei due laboratori
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