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Solid Tumour Section
Review
Fallopian tube tumors: an overview
Roland Gregor Stein, Joachim Diessner, Arnd Hönig, Jörg Wischhusen, Johannes Dietl
Wurzburg University Hospital, Department of Obstetrics and Gynecology, Josef-Schneider-Str. 4, 97080
Wurzburg, Germany (RGS, JD, AH, JW, JD)
Published in Atlas Database: March 2013
Online updated version : http://AtlasGeneticsOncology.org/Tumors/FallopTubTumID5279.html
DOI: 10.4267/2042/51820
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2013 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Inevitably, the considerable overlap between ovarian
and fallopian tube carcinomas warrants some coverage
of ovarian cancer in this context. Nevertheless, as
ovarian carcinomas constitute a well-accepted clinical
entity (irrespective of their potential origin from the
fallopian tube) they shall largely be dealt with in a
separate place.
Identity
Introduction
This article shall give an overview of different tumors
occurring in the fallopian tube.
Though being a very rare location of primary or
exclusive tumor manifestation, the fallopian tube is
now receiving increased attention in gynecological
oncology since considerable evidence suggests that it
represents the site-of-origin of many (if not most)
serous pelvic carcinomas (Folkins et al., 2009; Dietl
and Wischhusen, 2011; Dietl et al., 2011; Seidman et
al., 2011; Vang et al., 2013).
Disease definition
A tumor is classified as primary fallopian tube tumor
when it is either restricted to this anatomical structure,
or when the fallopian tube is most affected whereas colocations such as ovary and uterus show lesser
involvement or a different histology (Alvarado-Cabrero
et al., 2003; Folkins et al., 2009).
As recent data indicate that the fallopian tube is the
site-of-origin of serous pelvic carcinomas (Folkins et
al., 2009; Dietl and Wischhusen, 2011; Dietl et al.,
2011; Seidman et al., 2011; Vang et al., 2013),
histological assessment of the respective involvement
of ovaries and fallopian tubes may not be sufficient to
distinguish between advanced stages of fallopian tube
and ovarian carcinomas (Kosary and Trimble, 2002).
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Classification
Note
Solid fallopian tube tumors can be subcategorized
based on origin and behavior.
The WHO classification distinguishes several groups of
solid tumors of the fallopian tube (Alvarado-Cabrero et
al., 2003) shown in Figure 1.
Classification
Staging
Malignant tumors of the fallopian tube are classified
according to the "Union International contre le cancer"
(UICC) and the "Fédération internationale de
Gynécologie et d'Obstétrique" (FIGO, Table 1 and 2).
The TNM classification is based on clinical and
pathological findings whereas the FIGO classification
requires a surgical staging (UICC, 2009; AJCC, 2010).
According to the TNM classification, the carcinomas of
the fallopian tube approximate different stages (Table 2).
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Figure 1: WHO Classification of solid tumors of the fallopian tube (Alvarado-Cabrero et al., 2003).
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Table 1: TNM and FIGO Classification of carcinomas of the fallopian tube (UICC, 2009). Table 2: Staging of fallopian tube carcinomas
(UICC, 2009).
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of symptoms - intermittent profuse serosanginous
vaginal
discharge, colicky pain relieved by discharge,
abdominal or pelvic mass - is reported in only 15% of
all patients (Ajithkumar et al., 2005). 5% of the patients
show a hydrops tubae profluens. Fallopian tube
carcinomas are diagnosed at earlier stages than
epithelial ovarian cancers (Peters et al., 1988; Rose et
al., 1990; Gadducci et al., 2001; Pectasides et al.,
2006). 10-36% show positive PAP smear tests with
intermittent detection of abnormal, suspicious or poorly
differentiated cells or glands (Ajithkumar et al., 2005).
In 80% of the advanced stages, peritoneal metastases
occur (Levite et al., 2001). Also haematogenous or
transluminal metastases were found (Yoonessi, 1979).
Bilateral tubal involvement has been described in 1027% of fallopian tube carcinomas (Schiller and
Silverberg, 1971; Hirai et al., 1989; Rose et al., 1990;
Alvarado-Cabrero et al., 1999; Rosen et al., 1999;
Gadducci et al., 2001).
The higher rate of lymph node metastases in
comparison to ovarian cancer should be considered, as
staging of fallopian tube carcinomas is surgical.
Compared to epithelial ovarian cancer, fallopian tube
carcinomas show a higher rate of retroperitoneal and
distant metastases (Yoonessi, 1979; McMurray et al.,
1986; Maxson et al., 1987; Asmussen et al., 1988;
Peters et al., 1988; Gadducci et al., 2001). Para-aortic
lymph node metastases were detected in 33% of
patients (Tamimi and Figge, 1981). Another study
revealed 42-59% lymph node metastases in routine
lymphonodectomy with equal involvement of paraaortic and pelvic lymph nodes (Ajithkumar et al.,
2005). If routine lymphonodectomy is not performed, a
surgical understaging may occur. Overall, 20-25% of
patients with fallopian tube carcinomas showed FIGO
stage I, 20% stage II, 45-50% stage III and 5-10% stage
IV (Ajithkumar et al., 2005).
Ectopic β-HCG-production was reported in two cases
of serous or undifferentiated fallopian tube carcinomas
(Carapeto et al., 1978; Alvarado-Cabrero et al., 1999).
These tumors contained syncytiotrophoblast-like cells.
Case reports about renin-producing or alpha fetoprotein
(AFP)-producing tumors have been published (Aoyama
al., 1996; Zabernigg et al., 1997).
Fallopian tube carcinomas show frequent expression of
CA-125 (Puls et al., 1993). Hence, >80% of the
patients show elevated CA-125 serum levels
(McMurray et al., 1986; Ajithkumar et al., 2005) that
correlate significantly with disease-free and overall
survival (Rosen et al., 1999; Ajithkumar et al., 2005).
Adenomyomas can also cause elevated CA-125 levels
and small volumes of serous ascites. With some
limitations, CA-125 may thus be considered as suitable
tumor marker for use in cancers of the fallopian tube
(Baekelandt et al., 2000).
Clinics and pathology
Etiology
The etiology of primary fallopian tube tumors is
unknown. Multiparity seems to be protective (Riska et
al., 2003), pregnancies and oral contraceptives decrease
the risk (Inal et al., 2004). Neither age, nor weight,
education level, pelvic inflammatory disease, infertility,
previous hysterectomy or endometriosis show
significant correlations especially with fallopian tube
carcinomas (Henderson et al., 1977; Demopoulos et al.,
2001; Inal et al., 2004). Demographic distribution is
similar to ovarian cancer, and the highest incidence was
found in white, non-Hispanic women and women aged
60-79. However, recent evidence suggests tubal cancer
to be much more frequent (Stewart et al., 2007; Piek et
al., 2008).
Epidemiology
Epidemiological data on malignant fallopian tube
tumors are adequate, even though only 0.3-1.1% of all
gynecological malignancies are typically classified as
primary fallopian tube carcinomas (Baekelandt et al.,
2000), mostly adenocarcinomas (Schneider et al.,
2000). In the U.S., the incidence is about 3.6 per
million women per year (Rosenblatt et al., 1989).
Stage-adjusted survival rates are generally better than
for epithelial ovarian carcinoma (Kosary and Trimble,
2002). Underestimation of the real incidence might be
due to fallopian tube carcinomas being mistaken for
ovarian cancers (Woolas et al., 1994) which show a
significantly higher prevalence. Still, Riska and
colleagues reported an increasing incidence of fallopian
tube carcinomas from 1.2 per million per year for 19531957 to 5.4 per million per year from 1993-1997 (Riska
et al., 2003).
Clinics
Clinical presentation
Patients with benign tumors of the fallopian tube are
often asymptomatic or report local pain. The tumors are
incidentally found during operations for other
indications (Etoh et al., 2012). Benign tumors can abet
tubal torsions (Alvarado-Cabrero et al., 2003).
Especially papillomas can obstruct the fallopian tube
(Gisser, 1986). Obstruction of the fallopian tube can
cause infertility (Heller et al., 1991; Heatley, 2001).
Primary fallopian tube carcinomas most frequently
occur between the fourth and sixth decade of life with a
mean patient age of 55 years (Boutselis and Thompson,
1971; Sedlis, 1978). Stewart et al. found an incidence
rate of 0.41 per 100000 women with highest incidence
rates in women aged 65-69 in a study including 3051
cases of primary fallopian tube carcinomas (Stewart et
al., 2007). Symptoms are very diffuse, the Latzko triad
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Figure 2: Histology of an invasive serous-papillary adenocarcinoma of the fallopian tube. a: Tumor formation in the tubal wall. b shows
200 fold magnification with gland formation (*). c: Metastasis in adipous tissue. d: Immunohistochemistry for Ki67 with nuclear positivity.
e and f: Immunohistochemistry for p53 also with nuclear positivity.
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Figure 3: a: In this H&E staining, the STIC cells show polymorphic nuclei and a multilayer epithelium (arrowheads) compared with
normal tubal epithelium (arrows). b: Distinct transition from normal tubal epithelium to p53 positive STIC (p53 immunohistochemistry). c:
Invasive fallopian tube carcinoma (arrowheads) next to STIC formation (arrows, H&E).
The average lead time of increasing CA-125 levels
versus clinical or radiological diagnosis of recurrence is
three months with a range from 0.5 to 7 months
(Ajithkumar et al., 2005).
Fallopian tube carcinomas can cause paraneoplastic
symptoms. For example, a paraneoplastic cerebellar
degeneration (PCD) with Anti-Yo antibodies is
associated with fallopian tube carcinomas (Levite et al.,
2001; Tanaka et al., 2005; Selby et al., 2011).
Cabrero et al., 2003). In fallopian tubes resected post
partum, few metaplastic papillary tumors were detected
(Saffos et al., 1980; Keeney and Thrasher, 1988;
Bartnik et al., 1989). These tumors consist of papillae
lined by epithelium displaying patterns of a serous
borderline tumor. The cells can be positive for
intracellular mucin (Alvarado-Cabrero et al., 2003).
Adenomyomas consist of bundle-like growing
leiomyoma cells and sometimes endometrial tissue
remnants.
Endometrioid polyps occur in the interstitial part of the
tube attached to the intratubal epithelium and
sometimes cause infertility (Heller et al., 1991;
Heatley, 2001).
Cystadenofibromas can show vimentin-cytokeratincoexpression. Further, diffuse apical epithelial
membrane antigen (EMA) immunoreactivity occurs.
Gürbüz et al. suggest that tumors are derived from
embryonic remnants of the Müllerian duct (Gürbüz and
Ozkara, 2003).
Borderline tumors of the fallopian tube occur very
rarely and can show serous, mucinous or endometrioid
differentiations. Histological features resemble those in
borderline tumors of the ovary (Alvarado-Cabrero et
al., 1997). Mucinous tumors of the fallopian tube can
Pathology
Benign tumors
Benign tumors are often solid and clearly delimited.
They arise at the intraluminal or serosal surface of the
fallopian tube.
Papillomas show fibrovascular stacks with epithelial
lining. They can obstruct the fallopian tube (Gisser,
1986).
Adenofibromas and cystadenofibromas occur between
the third and eighth decade. They remain asymptomatic
and are diagnosed incidentally during other operations
(Zheng et al., 1996). Macroscopically, these tumors
grow to 0.5-3cm and can be intraluminal or at the
serosa surface as well as at the fimbriae. They show a
stromal and a papillary structured fraction (Alvarado-
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development and already detectable in the STIC (Kuhn
et al., 2010).
As the post-reproductive fallopian tube lacks
physiological functions and also causes complications
such as hydrosalpinx, Dietl et al. suggested combined
hysterosalpingectomy instead of simple hystercectomy
or salpingectomy as a recommendable method for
sterilization in clinical routine (Dietl and Wischhusen,
2011; Dietl et al., 2011).
Invasive carcinoma
All tumor subtypes in the ovaries are also known in the
fallopian tube, with serous carcinomas being most
frequent. In a series of 105 fallopian tube carcinomas
Alvarado-Cabrero et al. found the following
distribution of different histologies: About 50% were
serous, 25% endometrioid, 20% transitional cell or
undifferentiated carcinomas and 5% were of other
subtypes (Alvarado-Cabrero et al., 1999).
Serous adenocarcinomas are generally invasive with
50% G3 tumors (Alvarado-Cabrero et al., 1999).
Sometimes immune cell invasion disguises the tumor
as salpingitis (Cheung et al., 1994).
Mucinous adenocarcinomas, a very rare entity, are
often associated with other mucinous carcinomas of the
female genital tract or the appendix (Seidman, 1994).
Endometrioid adenocarcinomas are very often noninvasive or superficially invasive and show a favorable
prognosis (Navani et al., 1996). A part of those tumors
displays characteristics of the wolffian adnexal tumor
(Daya et al., 1992; Navani et al., 1996).
Clear cell adenocarcinomas account for 2-10% of all
fallopian tube carcinomas (Voet and Lifshitz, 1982;
Hellstrom et al., 1994; Alvarado-Cabrero et al., 1999).
Transitional cell carcinomas are rare in the genital tract.
Still, the frequency between 11 and 43% of all fallopian
tube carcinomas makes it an important locus-specific
entity (Uehira et al., 1993; Alvarado-Cabrerog et al.,
1999).
Undifferentiated carcinomas lack any patterns of
squamous cells or glandular cells but instead contain
multinuclear giant cells (Alvarado-Cabrero et al.,
1999).
Lacy et al. reported immunohistochemical positivity for
c-erbB-2 (HER-2/neu) overexpression in 26% and p53
positivity in 61% of all cases in a cohort of 43 patients
with fallopian tube carcinoma. There was not
significant correlation with survival (Lacy et al., 1995).
Ovarian cancer in comparison also shows c-erbB-2
(HER-2/neu) positivity in about 29% of all cases
(Lanitis et al., 2012). Others, in contrast, described a
correlation between p53 immunohistochemical
positivity and shorter survival (Zheng et al., 1997;
Rosen et al., 2000). FIGO stages, however, did not
correlate with survival in this same cohort of 63
patients (Rosen et al., 2000). Zheng et al. investigated
the correlating immunohistochemistry and polymerase
chain
reaction-single-strand
conformation
polymorphism (PCR-SSCP) for p53 in 52 cases of
fallopian tube carcinoma and 10 normal fallopian tubes
be associated with pseudomyxoma peritonei (McCarthy
and Aga, 1988), other mucinous lesions or PeutzJeghers-Syndrome (Seidman, 1994). There are also
reports about adenofibroma
with borderline
malignancy. The prognosis seems to be favorable
(Zheng et al., 1996; Alvarado-Cabrero et al., 1997).
Precursor lesions: Intraepithelial carcinoma
Non-invasive carcinomas of the fallopian tube were
formerly known as "carcinoma in situ". This term
should be abandoned as it implies restricted local tumor
formation. Intraepithelial carcinoma cells can, however,
form implants on the ovarian surface and the
peritoneum. Recent publications highlight the fallopian
tube as likely site-of-origin of primary pelvic serous
carcinomas detected in the fallopian tube, the ovary or
the peritoneum (Folkins et al., 2009; Dietl and
Wischhusen, 2011; Dietl et al., 2011; Seidman et al.,
2011; Vang et al., 2013). Serous tubal intraepithelial
carcinomas (STIC) as well as endometrioid
intraepithelial carcinomas (EIC) are thus considered as
precursor lesions (Ambros et al., 1995; Carlson et al.,
2008). This hypothesis is supported by findings from
Colgan et al. who found a high frequency of precancerous lesions in fallopian tubes from patients with
BRCA gene mutations (Colgan, 2003). Lee and
colleagues could detect mutant p53-signatures
predominantly in epithelial cells at the fimbriated ends
of fallopian tubes from patients with BRCA1 and 2
mutations. Moreover, the same signatures were also
found in corresponding ovarian cancer tissues (Lee et
al., 2007). Interestingly, Li-Fraumeni-Syndrome which is associated with p53 mutations and generally
increased risk for serous carcinomas - does not
correlate with a higher incidence of PPSC, especially
fallopian tube carcinomas. Thus, it seems that other
mutations e.g. those affecting BRCA are required to
drive PPSC development (Xian et al., 2010). Kim and
colleagues could prove by histology that serous
epithelial cancers develop in the fallopian tubes of
Dicer-PTEN-double-knockout mice. By histology and
pathological
behavior
these
tumors
showed
characteristic traits of serous epithelial ovarian cancer,
even though oophorectomy was not protective. Instead,
tumor development could be prevented by
salpingectomy (Kim et al., 2012). Furthermore, in
prophylactic salpingo-oophorectomy specimen, occult
carcinomas are more frequent in the fallopian tube than
the ovary (Vang, 2011). While carrying the potential of
invasiveness, the STIC cells grow sparing the tubal
stroma. Figure 3 focusses on the STIC with its distinct
cellular alterations such as polymorphic nuclei,
multilayer epithelium and atypic mitoses. Figure 3d
also shows an invasive fallopian tube carcinoma with
an adjoining STIC.
In clinical studies, a frequent coexistence of pelvic
serous carcinoma and tubal intraepithelial carcinomas
was found in unselected (Przybycin et al., 2010) and
BRCA mutated patients (Kindelberger et al., 2007).
Shortening of telomeres is another early event in PPSC
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Fallopian tube tumors: an overview
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fallopian tube (Dekel et al., 1986). About 40% of these
go along with adnexal tumors (Ober and Maier, 1981).
In the fallopian tube, hydatiform moles can
histologically correspond to a complete, partial or
invasive mole (Alvarado-Cabrero et al., 2003).
Placental site nodules as non-neoplastic proliferation of
intermediate trophoblast can occur (Alvarado-Cabrero
et al., 2003). Intermediate trophoblast tumors can be
either benign or malignant (Kurman et al., 1976). Only
one case of malignant placental site trophoblastic tumor
has been reported in the fallopian tube (Su et al., 1999).
Lymphoid and haematopoietic tumors
Malignant lymphoma and leukemia mostly show an
involvement of the ipsilateral ovary (Osborne and
Robboy, 1983). 25% of patients with ovary lymphomas
had a Burkitt-lymphoma or Burkitt-like lymphoma or a
diffuse large-cell lymphoma.
Metastatic tumors
For 89% of secondary tumors in the fallopian tube, the
primary tumor was assigned to be of ovarian origin
(Woodruff and Julian, 1969). Considering the ongoing
paradigm shift which proposes that serous ovarian
carcinomas likely originate from the fallopian tube,
these figures have to be reconsidered. Many of these
tumors may have originated from the fimbriated end of
the fallopian tube with a secondary manifestation in the
ovary.
and found that p53 alterations already occur at early
stages suggesting a role in early tumor progression
(Zheng et al., 1997). Chung and colleagues found that
survival neither correlated with immunohistochemical
p53 positivity nor with cMyc overexpression (which
occured in 61%). However, the statistical power of this
study was limited by the small cohort of 18 patients
(Chung et al., 2000). Hence, it did not challenge larger
studies which proposed that p53 might have an
important role especially in familial BRCA-associated
cases of fallopian tube carcinomas. Figure 2 shows
different pathohistological aspects of a serous
adenocarcinoma of the fallopian tube.
Mixed epithelial-mesenchymal tumors
The least common site for malignant Müllerian mixed
tumor (carcinosarcoma, metaplastic carcinoma) is the
fallopian tube accounting for only 4% of all cases. The
prognosis of these mostly postmenopausal patients is
poor (Hanjani et al., 1980).
In the literature, only one adenosarcoma has been
described in the fallopian tube (Gollard et al., 1995).
Soft tissue tumors
Leiomyosarcomas are very rare as only 37 cases have
been reported in 100 years (Jacoby et al., 1993).
Mesothelial tumors
Adenomatoid tumors mostly occur in middle-aged or
elderly women (Inoue et al., 2001). In most cases, they
remain asymptomatic but can also occlude the lumen.
Often, they show gland-like structures with a lining of
flat to cuboidal cells (Stephenson and Mills, 1986).
Germ cell tumors
Until 2003, 50 cases of mature or immature teratoma
were reported (Alvarado-Cabrero et al.,
2003). For malignant mixed germ cell tumors of the
fallopian tube, only one single case was published (Li
et al., 1999).
Trophoblastic tumors
Only about 4% of choriocarcinomas occur in the
Treatment
Surgical therapy: For fallopian tube tumors and
especially for carcinomas, surgical removal is the first
line treatment. Whereas benign tumors can usually be
resected completely, the approach for fallopian tube
carcinomas should be the same as for epithelial ovarian
cancer with the aim of complete resection or at least
maximum tumor debulking.
Table 3: Postoperative treatment of fallopian tube carcinoma (Pectasides et al., 2006).
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platinum-pretreated patients also highlights the role of
Paclitaxel (Tresukosol et al., 1995; Baekelandt et al.,
2000; Ichikawa et al., 2000; Gemignani et al., 2001).
After review of the literature and according to the U.S.
guidelines, Pectasides and colleagues suggested an
adjuvant standard treatment shown in table 3
(Pectasides et al., 2006).
For the treatment of relapse, platinum-sensitive tumors
(relapse after more than 6 months) receive a
reinduction with platinum with or without Paclitaxel,
whereas patients with platinum-refractory (relapse
during therapy) or platinum-resistant tumors (relapse
<6 months) receive Topotecan or liposomal
Doxorubicin (Pectasides et al., 2006). In epithelial
ovarian cancer, Bookman and colleagues as well as
Hoskins et al. treated patients with relapse after
platinum- and Paclitaxel-based chemotherapy with
Topotecan (Bookman et al., 1998; Hoskins et al.,
1998). Also liposomal Doxorubicin can achieve
response rates of 17-26% in patients who have relapsed
after platinum- and Paclitaxel based chemotherapy
(Muggia et al., 1997; Gordon et al., 2000). Recent data
from the OCEANS trial revealed that addition of
Bevacizumab
to
the
combination
of
carboplatinum/gemcitabine increases the response rate
and prolongs progression-free survival in patients with
platinum-sensitive
recurrent
ovarian,
primary
peritoneal, or fallopian tube cancer. Overall survival,
however, remained unchanged (Aghajanian et al.,
2012).
Likewise, the CALYPSO trial which tested the
combination of pegylated liposomal doxorubicin
(PLD)/carboplatin with paclitaxel/carboplatin in
platinum-sensitive ovarian cancer patients found a
prolonged time to progression along with reduced side
effects of PLD as compared to paclitaxel. Again,
however, there was no effect on overall survival
(Wagner et al., 2012).
Still, an intermediate report from the AURELIA trial
suggests that supplementation of chemotherapy with
Bevacizumab might be highly beneficial for patients
with platinum-resistant ovarian cancer (PujadeLauraine et al., 2012).
Special focus should be placed on para-aortic and
pelvic lymphadenectomy in regard to the higher rate of
lymph node metastases (Yoonessi, 1979; McMurray et
al., 1986; Maxson et al., 1987; Asmussen et al., 1988;
Peters et al., 1988; Gadducci et al., 2001).
Klein and colleagues found a significantly reduced
median survival of 21 months versus 43 months in
patients who had not undergone lymphadenectomy
(Klein et al., 1999).
Radiotherapy: Although radiotherapy for fallopian
tube carcinomas could be considered, it is inferior to
adjuvant platin compounds containing chemotherapy.
Neither irradiation nor intraperitoneal instillation of
radioisotopes could prevent relapse (Asmussen et al.,
1988). A second look operation with pathological
complete remission (pCR) is a predictor for longer
survival. 50% of patients with surgical complete
remission will ultimately relapse. Thus, second-look
operations are not generally beneficial and hence no
routine treatment (Takeshima and Hasumi, 2000).
Adjuvant chemotherapy: Baekeland et al. found a
70% response rate to adjuvant platinum-containing
chemotherapy in platinum-naive patients with median
response duration of 12.5 months. They further
suggested to refrain from postoperative radiation
therapy due to its low efficacy and high rate of
complications (Baekelandt et al., 2000). Kosary et al.
gave the general recommendation to treat women with
fallopian tube carcinomas like women with epithelial
ovarian cancer, i.e. by surgical staging and debulking
followed by adjuvant chemotherapy (Kosary and
Trimble, 2002). In addition to platinum-based
chemotherapy, also paclitaxel is becoming more and
more important in the treatment of advanced fallopian
tube tumors (Takeshima and Hasumi, 2000). Patients
with early stages as IA and IB might not need adjuvant
chemotherapy. For all higher stages, adjuvant
combined chemotherapy is requested. Two randomized
controlled trials (International Collaborative Ovarian
Neoplasm 1 (ICON1) and Adjuvant Chemotherapy In
Ovarian Neoplasm (ACTION)) compared platinum
based adjuvant chemotherapy and mere observation
after early stage ovarian cancer surgery and reported 5
year overall survival rates of 74% without and 82%
with adjuvant platinum based chemotherapy (Trimbos
et al., 2003).
This could hint at a survival benefit being associated
with adjuvant chemotherapy also for early stage
fallopian
tube
carcinomas.
Cisplatin
based
chemotherapy yielded response rates between 53 and
92 % (Deppe et al., 1980; Raju et al., 1981; McMurray
et al., 1986; Maxson et al., 1987; Peters et al., 1988;
King et al., 1989; Muntz et al., 1989; Barakat et al.,
1993; Pectasides et al., 1994). Several studies also
included Paclitaxel in the first line therapy (McMurray
et al., 1986; Maxson et al., 1987; Muntz et al., 1991;
Ben-Hur et al., 1999; Gemignani et al., 2001). For
relapse therapy, data from epithelial ovarian cancer in
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Prognosis
Prognostic factors for early stage I carcinomas are
depth of invasion into the tubal wall and tumor rupture
during surgery. Even early stages tend to metastasize to
the peritoneum (Baekelandt et al., 2000).
The surgical stage is an independent prognostic factor
(Alvarado-Cabrero et al., 1999; Baekelandt et al.,
2000). Carcinomas of the fimbriae region are afflicted
by a worse prognosis than carcinomas of the isthmic
region (Alvarado-Cabrero et al., 1997).
There are different results concerning the histological
grading: Vaughan et al. found a significant correlation
between grading and survival (Vaughan et al., 1998),
Gadducci et al. could also find this in univariate but not
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Fallopian tube tumors: an overview
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in multivariate analysis (Gadducci et al., 2001).
Grading further correlates with lymphogenous
metastases (Klein et al., 1999). Lymphocytic
infiltration of the tumor correlates with favorable
outcome (Rosen et al., 1993). The role of DNA-ploidy
is thought to be negligible (Klein et al., 2002).
Fallopian tube carcinoma patients show an overall
survival of 30-50% which is slightly better than the
reported 25-40% for epithelial ovarian cancer
(Momtazee and Kempson, 1968; Baekelandt et al.,
1993; Barakat et al., 1993; Woolas et al., 1994;
Alvarado-Cabrero et al., 1999; Piura and Rabinovich,
2000).
The general 5-year survival rate is about 65% (Sedlis,
1978; Deppe et al., 1980; Inal et al., 2004). Kosary and
colleagues found in a cohort of 416 women with
fallopian tube carcinoma 5 year-survival rates of 95%
for stage I (n=102), 75% for stage II (n=29), 69% for
stage III (n= 52) and 45% for stage IV (n=151) (Kosary
and Trimble, 2002).
that these areas may contain putative tumor suppressor
genes (Jongsma et al., 2002).
Different
authors
(see
above)
found
that
immunohistochemical or PCR-based positivity for p53
alterations correlates with shorter survival (Hellstrom et
al., 1994; Zheng et al., 1997; Rosen et al., 2000).
Genetics
BRCA1 (breast cancer 1, early onset)
Note
Fallopian tube carcinomas can manifest as a
consequence of the hereditary breast-ovarian cancer
syndrome. They are associated with BRCA1 and
BRCA2 mutations. In a cohort of 44 cases of fallopian
tube carcinoma, 11% of the patients were positive for
BRCA1 mutation and 5% were positive for BRCA2
mutations. Of the patients who received their diagnosis
before the age of 55 years, 28% (5/18) were BRCA
positive. First degree relatives of fallopian tube cancer
patients show an increased risk for early breast and
ovarian cancer (Aziz et al., 2001).
A BRCA1-carrier patient undergoing prophylactic
salpingo-oophorectomy showed a fallopian tube cancer
(Hartley et al., 2000). A positive family history of
fallopian tube carcinoma was predictive for BRCA1
mutation in 26 Canadian breast-ovarian cancer families
(Tonin et al., 1995). Friedman et al. reported fallopian
tube carcinomas in 2 of 12 families with BRCA1
mutations (Friedman et al., 1995). Tonin et al. found
BRCA1 mutations in four Ashkenazi Jewish breastovarian cancer families with fallopian tube carcinoma
(Tonin et al., 1996). Zweemer and colleagues detected
fallopian tube carcinomas in 2 of 23 families with
known BRCA1 mutations (Zweemer et al., 2000).
Thus, genetic evaluation should become part of the
diagnostics for patients with fallopian tube carcinomas.
In risk patients, prophylactic oophorectomy should be
accompanied by salpingectomy (Aziz et al., 2001).
And whether salpingectomy without oophorectomy is
sufficient treatment will be analyzed in the clinical
trials yet to come.
Jongsma and colleagues reported frequent loss of
heterozygosity (LOH) on chromosome 13 in BRCA1associated cases of fallopian tube carcinomas indicating
Location
17q21
DNA / RNA
6 different mRNA variants that undergo alternative
splicing. Splicing influences intracellular function and
location. According to ENTREZ Gene, BRCA1 starts
at NC_000017.10 (41196312..41277500, complement),
Spidey (mRNA to genomic sequence alignment tool,
http://www.ncbi.nlm.nih.gov/spidey) finds 24 exons.
The mRNA consists of ~81.2kb.
Protein
The encoded protein functions as intracellular tumor
suppressor
with
E3-ubiquitin
ligaseand
phosphopeptide binding activity. As a transcription
factor, it is a DNA damage sensor forming (together
with other proteins) the BRCA1-associated genome
surveillance complex (BASC). Germline mutations
lead to the familiar breast and ovarian cancer syndrome
with highly increased risk for cancer development.
Working together with RNA polymerase II, the protein
has an important role in transcription, DNA repair of
double-stranded breaks, and recombination.
There are five different protein isoforms. Isoform 1 is
the biggest with 1863 amino acids and 220 kDa. The
highest expression of BRCA1 is found in the ovaries,
thymus and testes.
Atlas Genet Cytogenet Oncol Haematol. 2013; 17(11)
Cytogenetics
Note
In BRCA1-related cases of ovarian and fallopian tube
carcinoma, loss of heterozygosity (LOH) studies
revealed high LOH frequencies on chromosome 13q11,
13q14, 13q21, 13q22-23, 13q32 and 13q32-4 that were
independent of type of BRCA1 mutation, stage and
grade.
The authors suggested the long arm of chromosome 13
to contain putative tumor suppressor genes (Jongsma et
al., 2002).
Genes involved and proteins
BRCA2 (breast cancer 2, early onset)
Location
13q12.3
DNA / RNA
According to Spidey, BRCA2 has 27 exons. The
mRNA spans about 84.2 kb.
In exon 11, the BRC repeats are encoded.
782
Fallopian tube tumors: an overview
Stein RG, et al.
Protein
Also BRCA2 is involved in DNA stability, especially
the double strand repair.
The several BRC motifs in the protein bind the RAD51
recombinase and thus enable DNA repair. The protein
consists of 3418 amino acids with a weight of 384 kDa.
Note
Tumor protein p53.
DNA / RNA
11 exons, 8 transcript variants encoding 7 protein
isoforms
(http://www.ncbi.nlm.nih.gov/gene/7157#referencesequences).
Protein
p53 is a tumor suppressor protein that is synthesized in
response to cellular stress. It causes cell cycle arrest,
apoptosis, senescence, DNA repair, or changes in
metabolism via DNA binding. The binding of p53 leads
to transcriptional activation of several genes. Mutations
are known from several human tumors and also for
hereditary tumor syndroms like Li-FraumeniSyndrome. Transcription activation is triggered by a
homo-tetrameric p53 complex in which mutant
isoforms are dominant over the wild-type protein.
Moreover, functional p53 induces its own degradation
(with a half-life of 15-30 min) whereas mutant p53
accumulates and thus enables immunohistochemical
detection.
Examining a cohort of 43 patients with fallopian tube
carcinoma, Lacy et al. found immunohistochemical
positivity for c-erbB-2 (HER-2/neu) overexpression in
26% and p53 positivity in 61% of these tumors, but no
significant correlation with survival (Lacy et al., 1995).
Others, however, described p53 immunohistochemical
positivity to be associated with shorter survival (Zheng
et al., 1997; Rosen et al., 2000) whereas FIGO stages
were not predictive for the outcome in this cohort of 63
patients (Rosen et al., 2000).
Using 52 cases of fallopian tube carcinoma and 10
normal fallopian tubes, Zheng et al. investigated the
p53 status based on immunohistochemistry and
polymerase chain reaction-single-strand conformation
polymorphisms (PCR-SSCP) and suggested that p53
alterations play a role in early tumor progression as
they are not restricted to late stages (Zheng et al.,
1997).
Chung and colleagues found that survival neither
correlated with immunohistochemical p53 positivity
nor with cMyc overexpression (which occured in 61%).
However, the statistical power of this study was limited
by the small cohort of 18 patients (Chung et al., 2000).
STK11 (serine/threonine kinase 11)
Location
19p13.3
Note
Mutation of this tumor suppressor gene causes the
autosomal dominant Peutz-Jeghers-Syndrome which is
characterized by intestinal polyposis and pigmented
naevi as well as increased tumor risk (Jeghers et al.,
1949; Giardiello et al., 1987). The protein is regulated
by androgens and estrogen in adipocytes (McInnes et
al., 2012).
DNA / RNA
The gene consists of 10 exons which encompass 23 kb.
Protein
The protein regulates cell polarity and functions as a
tumor suppressor. It consists of 433 amino acids with a
weight of 48.6 kDa.
ERBB2 (v-erb-b2 erythroblastic
leukemia viral oncogene homolog 2,
neuro/glioblastoma derived oncogene
homolog (avian))
Location
17q12
Note
Other names: HER-2/neu, c-erbB-2.
DNA / RNA
31 exons, 2 mRNA variants encoding 2 proteins:
isoform a and b.
Protein
This protein is a member of the epidermal growth
factor receptor (EGFR) family of receptor tyrosine
kinases. It forms heterodimers with other EGFRs that
(unlike ErbB-2) have a ligand binding domain and can
thus initiate intracellular signaling leading to activation
of pathways such as mTOR or PI3K. Overexpression is
known for several cancers such as breast and ovarian
but also fallopian tube carcinomas.
Based on a cohort of 43 patients with fallopian tube
carcinoma, Lacy et al. reported immunohistochemical
positivity for c-erbB-2 (HER-2/neu) overexpression in
26% and p53 positivity in 61% of all cases. They could
not find any correlation with survival (Lacy et al.,
1995).
MYC (v-myc myelocytomatosis viral
oncogene homolog (avian))
Location
8q24
DNA / RNA
3 exons, 1 variant, 1 isoform.
Protein
The protein plays a role in cell cycle and apoptosis. It
functions as transcription factor. Overexpression is
known in several cancers especially leukaemias and
TP53 (tumor protein p53)
Location
17p13.1
Atlas Genet Cytogenet Oncol Haematol. 2013; 17(11)
783
Fallopian tube tumors: an overview
Stein RG, et al.
Tamimi HK, Figge DC. Adenocarcinoma of the uterine tube:
potential for lymph node metastases. Am J Obstet Gynecol.
1981 Sep 15;141(2):132-7
lymphomas like Burkitt's lymphoma. Chung and
colleagues found that survival neither correlated with
immunohistochemical p53 positivity nor with cMyc
overexpression (which occured in 61%). However, the
statistical power of this study was limited by the small
cohort of 18 patients (Chung et al., 2000).
Voet RL, Lifshitz S. Primary clear cell adenocarcinoma of the
fallopian tube: light microscopic and ultrastructural findings. Int
J Gynecol Pathol. 1982;1(3):292-8
Osborne BM, Robboy SJ. Lymphomas or leukemia presenting
as ovarian tumors. An analysis of 42 cases. Cancer. 1983 Nov
15;52(10):1933-43
To be noted
Note
Acknowledgement: We would like to thank Prof. Dr.
med. Eva Geißinger and Dr. med. Camelia-Maria
Monoranu, Institute of Pathology at Würzburg
University, for supporting this publication with
histopathological material and helpful discussions.
Dekel A, van Iddekinge B, Isaacson C, Dicker D, Feldberg D,
Goldman J. Primary choriocarcinoma of the fallopian tube.
Report of a case with survival and postoperative delivery.
Review of the literature. Obstet Gynecol Surv. 1986
Mar;41(3):142-8
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This article should be referenced as such:
Stein RG, Diessner J, Hönig A, Wischhusen J, Dietl J.
Fallopian tube tumors: an overview. Atlas Genet Cytogenet
Oncol Haematol. 2013; 17(11):773-787.
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