SARCOMI UTERINI Fattori di Rischio

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SARCOMI UTERINIFattori di Rischio

• Franco Odicino
• Spedali Civili di Brescia

Caravaggio, 15 Maggio 2008
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Gynecological Sarcoma

• Soft tissue sarcomas (STSs)
• lt1 of all malignant tumors in the female tract
• Non-GISTs tumors (large and heterogeneous group)
• Uterine Leiomyosarcoma (0.64/100.000)
• Endometrial Stromal Sarcoma (0.19/100.000)
• Carcinosarcoma (Mixed Malignant Müllerian
  Tumor)(metaplastic carcinoma)
• Others (liposarcoma, pleomorphic sarcoma,
  angiosarcoma)(rare)
• Gastrointestinal stromal tumors (GISTs) (mutation
  in the c-kit gene encoding KIT receptor
  (transmembrane TK) ? imatinib)(rare)
  (vulvovaginal /rectovaginal septal mass)
• Small blue round cell tumors (major sensitivity
  to chemotherapy)(rare)
• Ewing tumor like sarcoma
• Primitive neuroectodermal tumor-like sarcoma
• Desmoplastic small blue round cell sarcoma
• Embryonal rhabdomyosarcoma

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RISK FACTOR

• A clearly defined occurrence or characteristic
  that has been associated with the increased rate
  of a subsequently occurring disease.
• Something which increases risk or susceptibility
• A characteristic, condition, or behavior that
  increases the possibility of disease or injury.
• An aspect of personal behavior or lifestyle,
  environmental exposure, or inborn or inherited
  characteristic, which, on the basis of
  epidemiologic evidence, is known to be associated
  with a health-related condition considered
  important to prevent.
• A characteristic statistically associated with,
  although not necessarily causally related to, an
  increased risk of morbidity.

Medical Dictionary Online
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UTERINE SARCOMARISK FACTORS

• Age
• Race social class differences
• Genetics
• Early menarche - late menopause
• Pre-existing chronic diseases
• Benign gynecologic diseases
• Other malignant diseases
• History of pelvic radiation
• Obesity
• Nulliparity infertility
• Use of tamoxifen
• Certain type of HRT

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UTERINE SARCOMARISK FACTORS

• Age
• Race social class differences
• Genetics
• Early menarche - late menopause
• Pre-existing chronic diseases
• Benign gynecologic diseases
• Other malignant diseases
• History of pelvic radiation
• Obesity
• Nulliparity infertility
• Use of tamoxifen
• Certain type of HRT

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UTERINE SARCOMARISK FACTORS

• Age
• Race social class differences
• Genetics
• Early menarche - late menopause
• Pre-existing chronic diseases
• Benign gynecologic diseases
• Other malignant diseases
• History of pelvic radiation
• Obesity
• Nulliparity infertility
• Use of tamoxifen
• Certain type of HRT

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Racial disparities in the patterns of care and
outcome for uterine neoplasms
J. D. Wright, J. Fiorelli, C. J. Cohen, P. B.
Schiff, W. M. Burke, A. L. Kansler, T.J. Herzog.
SGO Annual Meeting 2008. Abs 65

• The Surveillance, Epidemiology, and End Results
  (SEER) database was used to identify women with
  invasive uterine neoplasms diagnosed from 1988 to
  2004. Patients were stratified by histology into
  the following categories endometrioid, serous,
  clear cell, and sarcoma

76.953 WOMEN
plt0,0001
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• Artifactual explanations
• Lead-time bias
• Confounding explanations
• Race is liable to affect social class whereas
  social class will not affect race
• Causal explanations
• General mortality from other causes (use of
  general life-tables)
• Specific
• Stage at diagnosis
• Treatment (choice and quality)
• Tumor characteristics
• Host factors

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• 2677 Uterine Sarcomas (SEER program of the
  National Cancer Institute)
• 2098 white
• 420 black
• 159 other races.
• White women were significantly older at the time
  of diagnosis compared to blacks (64.2 vs. 62.7, p
  lt 0.05)
• The age-adjusted incidence rate of uterine
  sarcoma in black women was nearly twofold greater
  than of white women (7.0/105 vs. 3.6/105, p lt
  0.05).

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UTERINE SARCOMARISK FACTORS

• Age
• Race social class differences
• Genetics
• Early menarche - late menopause
• Pre-existing chronic diseases
• Benign gynecologic diseases
• Other malignant diseases
• History of pelvic radiation
• Obesity
• Nulliparity infertility
• Use of tamoxifen
• Certain type of HRT

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• LM Chromosomal imbalances 8/12 (66.7)
• Gains a 9q34 and chromosome 19
• Gains and losses of chromosome 1p
• Losses on 1p
• Gains on 12q

• LMS Chromosomal aberrations 8/8 (100)
• Chromosome 1 imbalances very prominent
• Losses on 14q and 22q
• Gains on chromosomes 8, 17 and X
• Chromosome arms over-represented 12q and 19p

The absence of specific abnormalities common to
all LM and LMS argues against their being
benigne-malignant counterparts
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UTERINE LEIOMYOMAS CYTOGENETIC CATHEGORIES
ACCORDING TO CHROMOSOMA ABNORMALITIES
University of Brescia, 2001
RESULTS
42
50
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Hereditary Cancer Syndromeslinked to LM/LMS

• Reed Syndrome/multiple cutaneous and uterine
  leiomyomatosis syndrome
• MCUL1 or MCL - autosomal dominant, incomplete
  penetrance
• Hereditary leiomyomatosis and renal cell
  carcinoma (HLRCC) syndrome
• heterozygous germline mutations in Fumarate
  Hydratase at 1q42
• Tuberous sclerosis complex (TSC)
• loss of function of the TSC2 gene product tuberin
• Birt-Hogg-Dubè (BHD) syndromes
• BHD is a term used to describe a genetic syndrome
  which was originally identified in 1977 as a skin
  disorder by three Canadian doctors Birt, Hogg,
  and Dubè autosomal dominant germ-line mutation
  Bhd gene h17p11.2

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UTERINE SARCOMARISK FACTORS

• Age
• Race social class differences
• Genetics
• Early menarche - late menopause
• Pre-existing chronic diseases
• Benign gynecologic diseases
• Other malignant diseases
• History of pelvic radiation
• Obesity
• Nulliparity infertility
• Use of tamoxifen
• Certain type of HRT

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From the Danish Cancer Register, 2,491 incident
invasive ovarian cancers, 860 borderline ovarian
tumors and 1,398 uterine cancers were diagnosed
between January 1, 1978 and December 31, 1998
among female residents of Denmark who were born
after 1936 (case group). A subsample of the
population, randomly chosen from the Central
Population Register comprised 99,812 women also
born after 1936 and living in Denmark at study
entry (January 1, 1978). Relative Risks (RR)
were derived togheter with 95 confidence
intervals associated with overall and
histology-specific tumor risks after adjustment
for calendar time and reproductive
characteristics.
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ULM ULMS

• ULM
• Present in 77 of reproductive age women with an
  average of 6.5 tumors per uterus
• Cramer, S.F. and Patel, A. (1990) The frequency
  of uterine leiomyomas. Am. J. Clin. Pathol., 94,
  435438.
• ULMS
• Very rare with an estimated annual incidence of
  0.64/100.000 women
• Harlow, B.L., Weiss, N.S. and Lofton, S. (1986)
  The epidemiology of sarcomas of the uterus. J.
  Natl. Cancer Inst., 76, 399402.
• Incidence of ULMS in hysterectomy specimen
  performed for ULM
• 0.13-0.29
• Leibsohn S, d'Ablaing G, Mischell Jr DR, Schaerth
  JB. Leiomyosarcoma in a series of hysterectomies
  performed for presumed uterine leiomyomas. Am J
  Obstet Gynecol 199016296874.
• It may be only a subset of leiomyomata that are
  likely to progress to leiomyosarcomas.
• The findings of this study suggest that the
  progression from ULM to ULMS may be more likely
  with cellular and symplastic ULM
• K. Mittal, A. Joutovsky Areas with benign
  morphologic and immunohistochemical features are
  associated with some uterine leiomyosarcomas
  Gynecologic Oncology 104 (2007) 362365

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ULM etiology
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ULMS etiology
A useful tool appliedhierarchical cluster
analysis These data raise the fascinating idea
that ULMS do indeed derive from UL and the
discrepancy in their frequency lies in the fact
that only rare histological and karyotypic
variants of UL may be amenable to malignant
progression. Recent exciting data have generated
the hypothesis that a small subset of UL with
variant histology and/or karyotype may represent
a premalignant transitional state while other UL
have greatly reduced malignant potential.
Nonetheless, relative to the rate of UL formation
in the population, the risk for MCL/HLRCC is
minimal, necessitating caution to avoid
unnecessary testing or alarm.
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ULM etiology
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UTERINE SARCOMARISK FACTORS

• Age
• Race social class differences
• Genetics
• Early menarche - late menopause
• Pre-existing chronic diseases
• Benign gynecologic diseases
• Other malignant diseases
• History of pelvic radiation
• Obesity
• Nulliparity infertility
• Use of tamoxifen
• Certain type of HRT

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Data were derived from a casecontrol study of
STS patients conducted between 1983 and 1998 in
the greater Milan area and the province of
Pordenone. Cases were comprised of 104 women.
Controls were 505 women. Data on menstrual and
reproductive factors (age at menarche, menstrual
pattern, menopause status, age at menopause,
spontaneous abortion, induced abortions, parity,
age at first pregnancy, age at first birth) were
derived using unconditional multiple logistic
regression models
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UTERINE SARCOMARISK FACTORS

• Age
• Race social class differences
• Genetics
• Early menarche - late menopause
• Pre-existing chronic diseases
• Benign gynecologic diseases
• Other malignant diseases
• History of pelvic radiation
• Obesity
• Nulliparity infertility
• Use of tamoxifen
• Certain type of HRT

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• A significantly elevated risk of sarcomas related
  to a prior diagnosis of thyroid diseases
  (RR2.78, 95CI 1.415.50)
• Hypertension was related to a non-significant
  elevation in the risk of sarcomas (RR2.69, 95CI
  0.987.41), although the increased risk was
  restricted to patients with short follow-up
  periods, possibly reflecting diagnostic biases
• Relationships of sarcomas with other diseases
  were difficult to interpret given small numbers
  of affected women (3 or fewer)
• Thyroid diseases are associated with a variety of
  alterations in steroid hormones

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UTERINE SARCOMARISK FACTORS

• Age
• Race social class differences
• Genetics
• Early menarche - late menopause
• Pre-existing chronic diseases
• Benign gynecologic diseases
• Other malignant diseases
• History of pelvic radiation
• Obesity
• Nulliparity infertility
• Use of tamoxifen
• Certain type of HRT

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Estimated worldwide patient exposureto tamoxifen
citrate

• More than 12 million patient years
• (information on file, AstraZeneca)
• Among these, 942 uterine malignancies were
  identified (48 in the US)
• Uterine Carcinomas 802 (85)
• Uterine Sarcomas 140 (15)
• 75 MMMT (32 fatal)

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Tamoxifen
It seems that the incidence of both common
adenocarcinoma and uterine sarcomas is increased
in women taking tamoxifen, with sarcomas making
up approximately 10 of total uterine
malignacies in these patients.
Fisher B, Costantino JP, Redmond CK, et al
Endometrial cancer in tamoxifen-treated breast
cancer patients Findings from the National
Surgical Adjuvant Breast and Bowel Project
(NSABP) B-14. J Natl Cancer Inst 86527-537, 1994
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p0.15
p0.04
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Increased Risk of Malignant Mullerian Tumor of
the Uterus Among Women With Breast Cancer Treated
by Tamoxifen C. Bouchardy, H.M. Verkooijen, G.
Fioretta, A.P. Sappino, G. VlastosJ Clin Oncol.
2002 Nov 120(21)4403Geneva Cancer Registry,
Institute for Social and Preventive Medicine,
University of GenevaGeneva University Hospitals,
Geneva, Switzerland
This study therefore confirms the strong
increased risk of MMMT uteri cancer among women
treated with tamoxifen and the importance of
their close surveillance.
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In conclusion, we provide population based
evidence that use of tamoxifen is associated with
an overall fourfold relative risk for MMMTs,
which rose to eight fold among long-term breast
cancer survivors, compared with the two fold risk
for endometrial adenocarcinomas.
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This current study is the first large,
population-based, multicenter study that has
validated this association of poor histologic
cell type uterine cancer.

• Of 52,109 women diagnosed with corpus uteri
  cancer, 1922 had a history of breast cancer
• Women with a history of breast cancer had a
  significantly higher proportion of uterine
  papillary serous carcinomas (UPSC) and sarcomas
  compared to those without a breast cancer history
  (9.4 vs. 6.3 for UPSC and 10.3 vs. 8.4 for
  sarcoma P lt 0.001)
• The association of breast cancer and poor
  prognostic uterine cancer cannot simply be
  explained by the age differences observed in the
  two groups
• There were no significant differences in the
  distribution of uterine histologic cell types
  between those with a history of ER vs. ER-
  breast cancers (p0.88).
• The time interval between the diagnosis of breast
  cancer to a poor histologic uterine cancer such
  as UPSC, clear cell, or sarcomas, was
  approximately 12 months longer than to an
  endometrioid uterine cancer (7.9 vs. 6.9 year
  plt0.001).

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BAX TGF?-RII IGF-IIR MSH3 MSH6
PTEN ?-catenin
MI
Endometrioid Ca
High grade endometrioid Ca
NE
Non-endometrioid Ca
P53
P53 LOH
P53 LOH
Carcinosarcoma
J.Prat
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UTERINE SARCOMARISK FACTORS

• Age
• Race social class differences
• Genetics
• Early menarche - late menopause
• Pre-existing chronic diseases
• Benign gynecologic diseases
• Other malignant diseases
• History of pelvic radiation
• Obesity
• Nulliparity infertility
• Use of tamoxifen
• Certain type of HRT

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as an IMRT treatment usually involves more
treatment fields, a bigger volume of normal
tissue will be exposed to lower radiation
doses. that IMRT may approximately double the
induced cancer rate compared with conventional
treatment.
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Altogether, IMRT is likely to almost double the
incidence of second malignancies compared with
conventional radiotherapy from about 1 to 1.75
for patients surviving 10 years. The numbers may
be larger for longer survival (or for younger
patients)
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GRAZIE
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CORPUS UTERI CANCER ( and MMT)
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UTERINE SARCOMA (1)(leiomyosarcomas)

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UTERINE SARCOMA (2)(endometrial stromal sarcomas
and adenosarcomas )