e r s

ESO-ESMO-RCE CLINICAL

n c
a
UPDATE ON RARE ADULT SOLID

c
CANCERS
Milan 25-27/11/2016

l i d
so
u lt Domenica Lorusso

a d Gynecologic Oncologic Unit

National Cancer Institute-Milan

a r e
CARCINOMA OF VULVA AND
VAGINA
R
 e r s
n c
c a
l i d
so
ult
a d
a r e
R
 Symptoms e r s
n c
•
•
Pruritis
Mass
45%
45% c a
• Pain 23%
l i d
•
•
Bleeding
Ulceration
s o
14%
14%

u lt
a d
• Patients delay medical care by 8 to 12 months
• Physicians delay biopsy by 6 to 10 months

a r e
R
 e r s
Do not forget!!!!!!
n c
c a
l i d
s o
u lt
a d
a r e
R
 TYPE OF VULVAR CANCER
e r s
n c
c a
l i d
s o
u lt
a d
a r e
R
 e r s
n c
c a
l i d
so
ult
a d
a r e
R
 Squamous Tumor: 2 Variants with
bifasic distribution e r s
n c
(15%)
c
(85%) a
l i d
so
u lt
a d
a r e
R
 e r s
n c
c a
l i d
so
ult
a d
a r e
R
 STAGE AS A PROGNOSTIC FACTOR r
e s
n c
c a
l i d
s o
u l t
a d
a r e
R
Vulvar Cancer – prognostic factors
e r s
n c
For nodal involvement
Size c a
Depth of invasion
l i d
Lesion thickness
s o
lt
Grade

du
Vascular space involvement
For survival

e a
Positive inguinal nodes

a r Positive pelvic nodes

R
 AGE AS A PROGNOSTIC FACTORS IN
e r s
VULVAR CANCER
n c
c a
l i d
so
u lt
a d
a r e
R
 VULVAR CANCER: TREATMENT
ALGORYTM e r s
n c
c a
l i d
so
ult
a d
a r e
R
 Treatment-SCC e r s
n c
dimension) c a
Stage IA (< 1 mm infiltration, < 2 cm

l i d
• Radical local excision without LN dissection

s o
• Inguinofemoral LN metastases : <1 %
lt
• Wide, deep excision of the lesion down to the
u
a d
inf. fascia of the urogenital diaphragm
• Clear margin: 2 cm (at least 1 cm)

a r e
R
 Nodal Status in T1 Vulvar Cancer
e r s
n c
Depth
<1 mm
Number
163
+ve nodes
0 c a %
0.0
1.1–2 mm 145
l i d
11 7.7
2.1-3 mm 131
s o 11 8.3
3.1-5 mm 101
u lt 27 26.7
>5 mm
TOTAL a d
38
578
13
62
34.2
10.7

a r e Hacker, Hoffman, Magrina, Parker, Wilkinson,

R Boice, Ross, Rowley, and Struyk.

 e r s
n c
c a
l i d
so
ult
a d
a r e
R
 r
SURGICAL MARGINS AS A PROGNOSTIC FACTOR IN VULVAR CANCER
e s
n c
c a
l i d
s o
u lt
a d
a r e
R
Treatment-SCC e r s
n c
invasion > 1 mm) c a
Stage IB (< 2 cm dimension , stromal

l i d
• Inguinofemoral LN metastases : >8 %

s o
• Radical local excision + ipslateral

u lt
inguinofemoral LN dissection ( lateralized
lesion) or bilateral inguinofemoral LN

a d
dissection (central lesions)

a r e
R
 LYNPHNODE INVOLVEMENT IS THE MOST

e
IMPORTANT PROGNOSTIC FACTOR IN VULVAR r s
CANCER
n c
c a
l i d
s o
u lt
a d
a r e
R
 5-YEAR SURVIVAL RELATED TO
CHARACTERISTICS OF POSITIVE NODES
e r s
n c
Diameter
Patients Survival %
c a P

< 5 mm 11
l i d
90.9
5 – 15 mm
> 15 mm
12
15
s o 41.6
20.6
.001

Site
u lt
Intra
Extra
a d 14
24
85.7
25.0 .001

r e
Prognostic value of pathological patterns of lymph node positivity in squamous

a
cell carcinoma of the vulva Stage III and IVA FIGO

R
Origoni M et al, Gynecol Oncol 1992;45: 313
 SLN METASTASIS DIMENSION AND PROGNOSIS
e r s
n c
c a
l i d
s o
u lt
a d
a r e
R
 e r s
n c
c a
l i d
so
ult
a d
a r e
R
 Advanced Vulvar Cancer
Management of Lymph Nodes
e r s
n c
a
CT Scan of groins, pelvis and abdomen

c
l i d Non-operable
No suspicious
o
Operable

s
suspicious nodes

lt
nodes (N0,N1)
(N2,N3) groin nodes

du
Complete groin
e a Resect bulky nodes Primary
chemoradiation

a r
dissection RT groin and pelvis Surgical resection

R
 Adjuvant RT Treatment
e r s
n c
• Positive margins
c a
• Positive Nodal Status l i d
– > 1 positive LFN
s o
lt
– 1 LFN with extra-capsular involvement
u
a d
a r e
R
 r
Death from Recurrence in an Undissected Groin
e s
Author Recurrence
n c
DOD
Rutledge (1970) 4
c a 3
Magrina (1979)
l
4
i d 3
Hoffman (1983)
s o 4 4

lt
Hacker (1984) 3 3

du
Monaghan (1984) 4 4

e a
Lingard (1992)
Case reports
7
10
7
8

a rTOTAL 36 32 (89%)
R
 e r s
n c
c a
l i d
so
ult
a d
a r e
R
 Sentinel Lymph Node
e r s
n c
c a
l i d
s o
u lt
a d
a r e
R
 e r s
n c
c a
l i d
so
ult
a d
a r e
R
 e r s
n c
c a
l i d
so
ult
a d
a r e
R
 e r s
n c
c a
l i d
so
ult
a d
a r e
R
 e r s
n c
c a
l i d
so
ult
a d
a r e
R
 e r s
n c
c a
l i d
so
ult
a d
a r e
R
Treatment-SCC e r s
n c
a
Stage II (> 2 cm dimension, negative LFNs)
c
l i
bilateral inguinofemoral d
• Modified radical vulvectomy + ipslateral /

lymphadenectomy
s o
lt
• Clear margin: at least 1 cm
u
a d
a r e
R
 e r s
n c
c a
l i d
so
ult
a d
a r e
R
 e r s
n c
c a
l i d
s o
ult
a d
a r e
R
부산백병원 산부인과
 Treatment-SCC
e r s
n c
organs and/or positive LFNs) c a
Stage III and IV (tumor infiltrating adjacent

l i d
• Radical vulvectomy combined with pelvic
o
exenteration high morbidity !!
s
lt
• Preoperative radiation therapy: downstage

du
the tumor, allow a more conservative surgery
• Chemoradiotherapy: locally advanced vulvar
a
cancer (cisplatin + 5-FU, Mitomycin + 5-FU
e
a r
R
 e r s
n c
c a
l i d
s o
u lt
a d
a r e Total pelvic exenteration

R Inguino-femoral lymphadenectomy……
 MANAGEMENT OF LOCALLY
ADVANCED DISEASE
e r s
n c
c a
l i d
so
ult
a d
a r e
R
 EXCLUSIVE CHEMORADIATION

e r s
-cCR: 27-75%, mean: 69.0%
n c
c a
-57.2% pts alive and NED (30-100%)

l i d
s o
u lt
a d
a r e
R
 GOG-205
e r s
n c
CT: Cis 40 mg/m2, weekly
RT: 1.8 Gy/fractions (57.6
c a
Gy)

l i d
s o
lt
Surgery in case of residual
disease (imaging/biopsy)

du
e a
a r
R 1 treatment related death, 9 discontinuations due to toxicity
 r
GOG-205
e s
n c
Response
c a
Clinical CR
l i d OS
Path CR (biopsy)
All
s o
u lt
a d
a r e
After a median Fup of 24 mts:

R Alive, NED: 51%

 EXCLUSIVE CHEMORADIATION
e r s
n c
a
Currently the most frequently used option
c
l i d
Allows to avoid surgery and associated morbidities

s o
lt
Modulation of toxicity needed (IMRT,
schedules?!?)
du
e a
a r
NEED TO SHARE AND ESTABLISH SCHEDULES
AND DRUGS!!!
R
 e r s
n c
c a
l i d
s o
u lt
a d
a r e
Recommended external irradiation for both internal and external genital
disease followed by excision of the tumour bed.
Richard Boronow 1973

R
NEO-ADJUVANT CHEMORADIATION: AIMS
e r s
n c
c a
Allows surgical resection in disease considered
unresectable
l i d
s o
lt
Reduce extent of surgery and associated
u
morbidity
a d
a r e
R
 NEO-ADJUVANT CHEMORADIATION

e r s
-pCR: mean: 48.0% (27-75%)
n c
-RS*: mean 77.2% (16-100%) c a
*no pelvectomy

l i d
s o
u lt
-Median Fup: 28 mts

a d -54% pts alive and NED (2-83%)

a r e -Recurrence rate: 32%

R
 NEO-ADJUVANT CHEMORADIATION
e r s
n c
c a
Good rates of response and surgery

l i d
s o
Prognostic advantage of the assessment
of pathR
u lt
a d
Deserves further exploration and comparison
r e
with other strategies
a
R
 NEO-ADJUVANT CHEMOTHERAPY

e r s
n c
c a
l i d
s o
u lt With a median

a d fup 49 mts,
69% alive NED

a r e
R
With CCNU (Bleo,MTX,lomustin) high toxicity and 7.5% mortality!!!
With CisP based, 86% response, 94% completed chemo, 77% surgery
 NEO-ADJUVANT CHEMOTHERAPY
e r s
-CCR: range 0-11%
-CPR: mean 56.7% (14-89%)
n c
-pCR: 11%,40%
c a
-RS*: mean 48.4% (0-100%)
l i d
Shift to platinum-based
*no pelvectomy

s o regimens encouraging!

u lt
a d
a r e
R
Preliminary evidence about platinum/PTX…..
e r s
n c
c a
N=10 pts

l i d
ORR: 80%
s o
3 cycles Cis/IFO or Cis/Paclitaxel

Surgery rate: 90%

u
MEDIAN PFS: 14 mts lt
a d
After 40 mts Fup: 55% pts alive NED
Manageable toxicity (40% grade 3-4 tox)

a r e
R
 NEO-ADJUVANT CHEMOTHERAPY
e r s
-CCR: range 0-11%
-CPR: mean 56.7% (14-89%)
n c
-pCR: 11%,40%
c a
-RS*: mean 48.4% (0-100%)
l i d
Shift to platinum-based
*no pelvectomy

s oregimens encouraging!

u lt
Cisplatin/Paclitaxel

a d
deserve further
exploration!

a r e
R
 Recurrent disease
e r s
• Local, inguinal or distant
n c
c a
i d
• 5-yr survival rate: according to location
l
-Perineal : 60 %
s
-Inguinal and pelvic : 27 %o
u
-Distant : 15 % lt
a d
a r e
R
 Recurrent Disease
e r s
n c
c a
• Local recurrence can be salvaged with
local excision
l i d
– 50% 5-year survival

s o
• Local Recurrence in Vulva
lt
– Reexcision or radiation and good prognosis if
u
a d
not in original site of tumor
– Poor prognosis if in original site

a r e
R
 Recurrence
e r s
n c
• Distal or Metastatic
• Distant disease is lethal c a
• Chemotherapy l i d
– Cisplatin
s
40% RR o
– Bleomycin
u lt 30% RR

a d
– Adriamycin 30% RR

a r e
R
 METASTATIC DISEASE
e r s
n c
c a
l i d
s o
u lt
a d
Unsatisfying results probably related to the
presence of previously treated patients

a r e (recurrent, persistent disease)

R
 METASTATIC DISEASE
-Median PFS: 1.3-10 mts
e r s
-Median OS: 3.2-19 mts
n c
-1yr OS: 30% c a
l i d
s o
u lt
a d
a r e Targeted agents

R little explored!!!
 e r s
n c
c a
l i d
s o
u lt
a d
r e
However, embryologic development of uterine cervix and cranial

a
vagina derive from Müllerian ducts (mesothelial surface) while

R vulva originate from ectoderma!

 Vulvar Melanoma
e r s
n c
c a
l i d
so
u lt
a d
a r e
R
 Melanoma
e r s
• 2nd common, 5% of
n c
primary, 3~7% of all
melanomas
c a
• Postmenopause, white,
nonHispanic
l i d
• 68 y/o
• Pigmented lesion
s o
minora
u lt
• Most clitoris or labia

a d
• RX: wide excision with
2 cm free border
• If depth of invasion

a r e
<1.5mm, 100%survival Melanoma of the vulva
involving the right
labium minus.

R
 Pagets Disease
e r s
n c
c a
l i d
s o
ult
a d
a r e
R
 Extramammary Paget’s disease r
e s
n c
•
• < 1%
c a
Intraepithelial adenocarcinoma

•
•
60~70 y/o

l i d
Pruritus (70%), eczematoid appearance, well-demarcated,

s
pale islands o
slightly raised edges with a red background, dotted with small

•
•
u l t
Dx.: Bx. Histopathology !
Persistent pruritus with no response to antieczema therapy

• d
within 6 weeks Bx. !!

a
Invasive adenocarcinoma may be beneath or within the
surface lesion synchronous neoplasm !!
•

a r e
30% will develop adenocarcinoma of the breast, colon, and
rectum

R
 Bartholin gland adenocarcinoma r
e s
n c
• Rare, 57 y/o
c a
• Duct lined by stratified squamous epi. which changes

i d
to transitional epi. as the terminal ducts are reached
l
s o
• If squamous lesion related to HPV infection !!
• Bartholin gland tumor in a postmenopausal women

l t
or > 40 y/o Bx. to survey the malignancy !!

u
• Metastasis is common (due to rich vascular and
d
lymphatic network)
a
a r e
R
 e r s
n c
c a
l i d
Vaginal Cancer
s o
u lt
a d
a r e
R
 Vaginal Cancer
e r s
n c
gynecologic malignancies
c a
• Rare tumor representing only 1-2% of all

l i d
• 80-90% are metastatic
Cervical
s o
Uterine
u
Colorectal lt
Ovary
a d
a r eVagina

R
 Pathological Types:
e r s
n c
• Secondary malignant tumors of the vagina are more common
than the primary tumors.
c a
l i d
• Vaginal SCCA may be considered primary if
there is neither cervical or vulvar CA at
s o
diagnosis or for 10 years prior
lt
• Mean age of patients with primary vaginal
u
d
cancer is 60-65 years
a
a r e
R
 Gross and microscopic Findings
e r s
• 50% of Vag Ca ulcerative n c
• 30% are exophytic
c a
l i d
• 20% are annular and constricting

s o
u lt
a d
a r e
R
 Staging
e r s
n c
Stage 0
Stage I c a
Carcinoma in situ, intraepithelial neolasia
Carcinoma limited to the vaginal wall
Stage II
l i d
Involved the subvaginal tissue but not extended to

s
lateral pelvic wall
o
Stage III
lt
Extended to pelvic wall

u
a d
Stage IV a Spread to adjacent organs or direct extension
beyond the true pelvis.

a r e
Stage IV b Spread to distant organs

R
 Staging e r s
n c
c a
l i d
s o
ult
a d
a r e
R
 5 Year Survival
e r s
n c
80
c a
70
60
l i d
50

s o
lt
40
30
20

du
e
0
a
10

r
Stage I Stage II Stage III Stage IV

Ra No correlation between grade and survival

 Natural History and Spread:
e r s
• Lesions usually found in the upper vagina on
n c
the posterior wall
c a
• Direct spread: into the local paravaginal tissues,
bladder, or rectum.
l i d
• Lymphatic spread:
s o
nodes.
u lt
– Lesions in the lower vagina: to the inguinal lymph

nodes.
a d
– Lesions in the upper vagina: to the pelvic lymph

r e
• Hematogenous spread: late event. Reach liver,
alung, bone.
R
 Lymphatic Drainage of Vagina
e r s
Lymphatic drainage
n c
of upper vagina via
pelvic nodes while
c a
lower vagina drains
via femoral and
l i d
inguinal nodes.
so
Any of the nodal
u lt
a d
groups may be
involved regardless
of the location of

r e
the tumor

a
R
 Vaginal Carcinoma
e r s
n c
•
•
Squamous Cell
Clear Cell
80-85%
10% c a
• Sarcoma l i d
3-4%
• Melanoma
so 2-3%

u lt
a d
a r e
R
 Squamous Vaginal Cancer precursors r
e s
n c
c
• 5% progress to Vaginal Ca
a
• VAIN – median age of VAIN 3 is 53 yrs

• VAIN 3
l i d
s o
– usually occurs in upper third of vagina and is

u l t
multifocal and diffuse in half the cases.
– CIN coexists w/ VAIN in 10-20% of pts

a d
– Colposcopic findings are similar to those of CIN
(aceto white epithelium with punctations and

a r emosaic patterns)

R
 Treatment:
e r s
• Management of stage 0 (in situ):
n c
– Topical fluorouracil for stage 0:
• It causes intense burning.
c a
l i d
• Long standing benefits is not proven yet
• Laser therapy

s o
• Primary localized tumors stage I (confined to the
vaginal wall):

u lt
– RT: a combination of external beam and brachytherapy.

a d
– Surgery: it is an alternative treatment for early lesions.
• Radical hysterectomy with upper vaginectomy, PLND may be used

a r e for lesions of the posterior and lateral vaginal fornices

R
 Management
e r s
n c
• Stage IIA
c a
– WPRT (2000cGy) + parametrial boost for 4500cGy-
5,000cGy total
l i d
o
– WPRT + combination of intracavitary and
s
lt
interstitial implants for 5000 to 6000 cGy total

u
• Stage IIB, III, IVA
d
a
– WPRT (4000 cGy) + parametrial boost (2500 cGy)

e
a r
R
 Verrucous Carcinoma
e r s
n c
occurs in the vagina c a
• Variant of well-differentiated SCCA that rarely

l i d
• Relatively large, well-circumscribed, soft

s
cauliflower-like mass o
lt
• Cytologic features of malignancy are lacking
u
a d
• May recur locally after surgery but rarely, if
ever, metastasizes

a r e
R
 Natural History and Patterns of
e r s
Failure
n c
• Stage I
c a
– 10-20% pelvic recurrence, 10-20% distant
• Stage II
l i d
o
– 35% pelvic recurrence, 22% distant
s
• Stage III

u lt
– 25-37% pelvic recurrence, 23% distant
• Stage IV
a d
– 58% pelvic recurrence, 30% distant

a r e
R
 Treatment of recurrence
e r s
n c
•
- Cisplatin
c a
CHEMOTHERAPY: THE SAME AS FOR CERVICAL CANCER

-
-
Paclitaxel
Navelbine
l i d
- Bleomicin
so
RR: 10-15%

u
Median PFS 1.8 months lt
d
Median OS 6 months
a
a r e
• BEST SUPPORTIVE CARE

R
 Clear Cell Adenocarcinoma and DES
e r s
Exposure
n c
• Incidence is between 0.14 to 1.4/1000 women
exposed to DES
c a
l i d
– DES used as anti abortifcant from 1949-1971
– 500+ cases confirmed by DES Registry

s o
u lt
• Median age at diagnosis 19 years
• Lesions found mainly in the upper 1/3 of the

a d
anterior vaginal wall
• 90% of patients with early stage disease (I and II)

a r e
at diagnosis

R
 Management
e r s
n c
• Clear Cell Adenocarcinoma
c a
– Surgery for stage I lesions has advantage of

i d
ovarian preservation and better vaginal function
l
following skin graft

s o
– Vaginectomy, radical hysterectomy PLND,

lt
paraaortic LNBx (frozen section of distal margin)

u
a d
– More extensive lesions: EBRT+ BRACHITERAPY

a r e
R
 Pathology
e r s
n c
• Melanoma
– 3nd most common vaginal cancer c a
l i d
– Most frequently found in the lower third

o
– Cells may be spindle shaped, epithelioid, or
s
lt
small lymphocyte-like, pigmented or non-
pigmented

du
– Junctional activity helps exclude the possibility

e a
of a metastasis

a r – Depth of invasion best predictor of survival

R
 Management
e r s
n c
• Small Cell Carcinoma
c a
– Reasonable local control may be obtained with

l i d
surgery or irradiation followed by systemic chemo

s o
u lt
– Cyclophosphamide, Adriamycin, Vincristine (CAV)
X 12 cycles (some prior to initiation of RT)

a d
a r e
R
 Management
e r s
n c
• Rhabdomyosarcoma
c a
– Generally treated with a combination of surgery,
RT, and chemotherapy
l i d
s o
– Local excision + intracavitary RT + systemic chemo

lt
has replaced radical pelvic surgery as therapy of
choice

du
e a
– Vincristine, Dactinomycin, Cyclophosphamide
(VAC) X 1-2 years effective adjuvant treatment for

a r stage 1 pz

R
 Management
e r s
n c
• Malignant Lymphoma
c a
– Vaginectomy and radical hysterectomy or pelvic

l i d
exenteration has been used for localized vaginal
tumors
s o
lt
– Satisfactory results with pelvic RT + systemic
chemo

du
– Cyclophosphamide, adriamycin, vincristine,

e a
prednisone (CHOP) X 6 cycles most often used

a r
R
 Vulva and Vagina tumors: NEEDS
e r s
MULTIMODAL APPROACH:
CHEMOTHERAPY
n c
INDIVIDUALIZED CARE

RADIOTHERAPY
SURGERY
c a
QUALITY OF LIFE

l i d
AGE

s o
u lt
a d
a r e COOPERATIVE
TRIALS

R
 e r s
n c
c a
l i d
s o
ult
a d
a r e
R
11/29/2016
4-D Ca Cx
Narayan