International Journal of Gynecological Pathology

34:275–280, Lippincott Williams & Wilkins, Baltimore

r 2015 International Society of Gynecological Pathologists

Original Article

Pseudoxanthomatous Salpingitis as an Ex Vivo Model

of Fallopian Tube Serous Carcinogenesis:
A Clinicopathologic Study of 49 Cases

Jeffrey D. Seidman, M.D. and Renee Woodburn, M.D.

Summary: Iron is a well-documented carcinogen based on both animal models and

observational studies in humans. There are limited published data on pseudoxanthom-
atous salpingitis, an uncommon condition characterized by the accumulation of
histiocytes containing iron and iron-related compounds—lipofuscin and hemosiderin—
in the lamina propria of the fallopian tube. The clinical and pathologic features of 49
consecutive cases were evaluated. The mean patient age was 53. A history of
endometriosis was found in 20%, infertility in 17%, and tubal ligation in 7%. Thirteen
(27%) had endometrial cancer and 2 patients had prior radiation therapy for cervical
carcinoma. Histologic evidence of endometriosis other than tubal pigment deposition
was identified in 65%, and in the fallopian tubes in 35%. Pigment deposition was
unilateral in 65% and multifocal or diffuse in 80%. Plasma cells, eosinophils, and
neutrophils were present in the tubal lamina propria in 57%, 18%, and 24%,
respectively. Hydrosalpinx was present in 51%. An iron stain was positive in
pseudoxanthoma cells lacking hemosiderin in 14 of 18 cases (78%). By immunohis-
tochemistry, 2 of 22 cases displayed p53 signatures. The Ki67 proliferation index was
elevated (410%) in 11 of 22 cases, with a mean index of 32% in those cases. An elevated
proliferation index did not correlate with inflammation. In summary, these findings
characterize the clinical and pathologic features of pseudoxanthomatous salpingitis and
confirm its close association with endometriosis, occasional association with radiation
therapy, and the presence of iron in the histiocytes. In view of the evolving paradigm
shift implicating the fallopian tubal epithelium as the site of origin of high-grade
extrauterine serous carcinoma, the presence of iron and iron-related compounds in the
fallopian tube provides an opportunity to study the early events in high-grade serous
carcinogenesis in a setting characterized by a well-documented carcinogen in close
anatomic proximity to the putative epithelium of origin. Key Words: Salpingitis—
Endometriosis—Iron—Lipofuscin—Hemosiderin—Pseudoxanthomatous inflamma-
tion—Carcinogenesis—Fallopian tube—Serous carcinoma—Ovarian carcinoma.

From the Departments of Pathology and Laboratory Medicine (J.D.S.); and Obstetrics and Gynecology (R.W.), Washington Hospital
Center, Washington, District of Columbia.
The opinions and assertions herein are the private views of the authors and do not reflect those of the FDA, Dept. of Health and Human
Services, or any other part of the US government.
This work is unrelated to J.D.S.’s employment at FDA. R.W. declares no conflict of interest.
Address correspondence to Jeffrey D. Seidman, MD, Molecular Pathology and Cytology Branch, Division of Molecular Genetics and
Pathology, Office of In Vitro Diagnostics and Radiological Health, Center for Devices and Radiological Health, Food and Drug
Administration, 10903 New Hampshire Ave., Silver Spring, MD 20993. E-mail: jeffrey.seidman@fda.hhs.gov.

275 DOI: 10.1097/PGP.0000000000000154

276 J.D. SEIDMAN AND R. WOODBURN
High-grade serous carcinoma causes the vast majority
of ovarian cancer deaths. Accumulating evidence
over the past decade supports an evolving paradigm
shift implicating the epithelium of the fallopian tubes
as the source of a majority of extrauterine high-grade
serous carcinomas. Accordingly, investigations of the
etiology and pathogenesis of ‘‘ovarian cancer’’ have
shifted to the fallopian tube (1–3).
The incessant ovulation hypothesis was proposed
over 4 decades ago to explain the direct correlation of
the risk of ovarian cancer with the length of
reproductive life uninterrupted by pregnancy. Re-
cently, Vercellini et al. (4) proposed that, in view of
the likely tubal origin, ‘‘ovarian cancer’’ risk is better
explained by the recognition that incessant ovulation
correlates with incessant menstruation, and that
menstruation and its almost constant accompani-
ment, menstrual reflux, is a source of tubal mucosal
exposure to carcinogens.
We recently reported that iron-containing com-
pounds are present in the mucosa of 20% of fallopian
tubes of women with advanced-stage high-grade
extrauterine serous carcinoma as compared with 5%
of a control group (Po0.001) (5). Iron is a well-
recognized carcinogen based on data from a variety of
animal models and observational data in humans
(5–10). Pseudoxanthomatous salpingitis (PXS) is an
uncommon condition characterized by the deposition
of iron-related pigment in the fallopian tubes. In the
current study, we evaluate a series of surgically
removed fallopian tubes with PXS which has, until
recently, been of interest primarily to investigators
focusing on endometriosis and infertility.
METHODS
Consecutive gynecologic surgical pathology acces-
sions from 2008 through 2013 at the Washington
Hospital Center were reviewed prospectively. All
fallopian tubes in which hemosiderin-laden macro-
phages and/or pseudoxanthoma cells were observed
in the lamina propria were included into the study.
Hemosiderin-laden macrophages were recognized by
course, brown refractile pigment within the cyto-
plasm of histiocytes. Pseudoxanthoma cells were
recognized by their finely granular, light brown,
nonrefractile pigment in the histiocytic cytoplasm.
Patients with ovarian, peritoneal, or tubal carcino-
mas were excluded and have been reported else-
where (5). Demographic and clinical data were
obtained from patient charts. All slides of fallopian
tubes and any accompanying ovaries and uteri were
Int J Gynecol Pathol Vol. 34, No. 3, May 2015
reviewed. In 14 cases, the fallopian tubes were
entirely embedded. In 35 cases, routine, random
sections of the tubes were processed. Microscopic
features assessed included the nature, focality, and
laterality of the pigment deposition, specific inflam-
matory cells present, and evidence of hydrosalpinx.
Focal was defined as one focus of pigment deposition
smaller than 5 mm. Diffuse pigment was defined as its
presence in multiple plicae in every section examined.
Those tubes that had more than focal pigment but
did not meet the criteria for diffuse pigment
deposition were considered to have multifocal pig-
ment deposition. In 23 cases, a representative block
was stained for iron (Prussian blue method). In 22
cases, a representative block was immunostained by
the avidin-biotin complex method with antibodies to
Ki67 (clone MIB-1; Dako, Carpinteria, CA) and p53
(Dako, clone DO-7). Nuclear staining was considered
positive. The proliferation index (PI) was determined
by counting the proportion of tubal epithelial nuclei
staining positive in the most active area. A p53
signature was defined as a contiguous stretch of 12
consecutive tubal secretory epithelial cells lacking
cytologic atypia and displaying nuclear positivity for
p53 protein at an intensity greater than the back-
ground wild-type staining of the epithelium (3).
RESULTS
A total of 49 patients were studied. The mean
patient age was 53 yr (median 50 yr; range, 25–80 yr).
Further clinical information was available in 46
patients. Twenty-one were premenopausal, 2 were
perimenopausal, and 23 were postmenopausal. There
was a clinical history of endometriosis in 9 patients
(20%) before the surgery that yielded the specimen
studied. More detailed endometriosis history was
available in 3 of these patients: there was a 2-, 7-, and
10-yr history of endometriosis, with Stage 4 endome-
triosis in the latter 2 patients. Eight (17%) had a
history of infertility. Three had tubal ligations. None
had a history of ectopic pregnancy, polycystic ovary
syndrome, or chronic anovulation. The mean grav-
idity was 3 (range, 0–9) and 8 had never been
pregnant. Two were known to have been on oral iron
supplements; however information on lifetime iron
intake was not available. Eleven were smokers, 3
abused alcohol, and 2 used illicit drugs. Four had a
history of breast cancer and 2 had cervical cancer
treated with radiation therapy. The latter 2 patents
had their salpingectomies 1 and 8 mo after comple-
tion of radiation therapy. Thirteen had endometrial
 PXS AS AN EX VIVO MODEL OF FALLOPIAN TUBE SEROUS CARCINOGENESIS 277

cancer (4 of these with endometrial carcinosarcomas);

PXS was diagnosed at the time of hysterectomy in all 13.
Operative findings included an enlarged or leio-
myomatous uterus in 23, adhesions in 18, adnexal
mass or cyst in 16, hydrosalpinx in 9, clubbed
fimbriae in 2, ascites in 2, and appendicitis, radiation
changes, and tubo-ovarian abscess in 1 each. A total
abdominal, laparoscopic-assisted vaginal, or robotic
hysterectomy was performed in 37 patients, bilateral
salpingo-oophorectomy in 33, unilateral salpingo-
oophorectomy in 8, ovarian cystectomy in 1, unilat-
eral salpingectomy in 7, bilateral salpingectomy in 1,
radical hysterectomy in 1, lymph node dissection in 8,
lysis of adhesions in 12, omentectomy in 3, appen-
dectomy in 3, cholecystectomy in 1, and sigmoid
FIG. 2. The tubal lamina propria contains hemosiderin-laden
resection in 1. macrophages with coarse brown refractile pigment.
Bilateral tubes were examined in 34 cases and 1
tube in 15 cases. The mean number of blocks of phils, or plasma cells) was present in 42 cases (86%).
fallopian tubes examined was 3.4 (median 3; range, In 3 cases, multinucleated giant cells were associated
1–9). Fimbrial tissue was present in 21 cases. with the pigmented histiocytes (Fig. 3).
Pseudoxanthoma cells alone were present in 35 cases, Other tubal pathology observed included salpingi-
hemosiderin alone in 3 cases, and both in 11 (Figs. 1, tis isthmica nodosa in 8 cases, salpingoliths in 3 (11),
2). Pigment deposition was unilateral in 22 of 34 cases tubo-ovarian abscess in 3, and adenomatoid tumor in
(65%) for which both tubes were examined. Pigment 1. One or both ovaries were examined in 42 cases.
deposition was focal, multifocal, or diffuse in 10, 26, Histologic evidence of endometriosis other than tubal
and 13 cases, respectively. In 41 cases for which a pigment deposition was present in 32 cases (65%).
fimbrial or nonfimbrial location could be ascertained, Endometriosis was seen in the ovaries in 18 cases
3 displayed fimbrial pigment alone, 32 nonfimbrial (37%), tubes in 17 cases (35%), and pelvic perito-
alone, and 6 both fimbrial and nonfimbrial. Evidence neum and/or broad ligament in 8 cases (16%). Other
of hydrosalpinx was seen in 25 cases (51%). Plasma ovarian lesions observed included serous cystadeno-
cells were present in 28 cases (57%), eosinophils in 9 ma in 4, mucinous metaplasia of surface epithelial
(18%), and neutrophils in 12 (24%). Evidence of inclusions in 2, and mucinous cystadenoma, atypical
acute or chronic salpingitis (hydrosalpinx, neutro- proliferative seromucinous tumor, Brenner tumor,

FIG. 1. Pseudoxanthomatous salpingitis characterized by filling of FIG. 3. Pseudoxanthoma cells in the tubal lamina propria are
the tubal lamina propria with macrophages containing finely intermixed with lymphocytes, multinucleated giant cells, and rare
granular light brown pigment. eosinophils and plasma cells.

Int J Gynecol Pathol Vol. 34, No. 3, May 2015

278 J.D. SEIDMAN AND R. WOODBURN
FIG. 4. Prussian blue iron stain shows the presence of iron in
pseudoxanthoma cells.
and mature cystic teratoma in 1 patient each. The
uterus was examined in 38 patients. Leiomyomas
were present in 18, endometrial hyperplasia or
carcinoma in 15, adenomyosis in 7, cervical carcinoma
in 2, HSIL in 2, endometritis in 2, and adenomatoid
tumor in 1. Among patients with endometrial or
cervical carcinoma, no tubal or ovarian metastases
were observed.
An iron stain was positive in 18 of 23 cases (78%).
Staining was relatively weak or focal in 7 of these.
Iron stain was positive in 14 of 18 cases (78%) that
had pseudoxanthoma cells without hemosiderin-
laden macrophages (Fig. 4). Immunostain for p53
displayed p53 signatures in 2 of 22 cases (9%). The
Ki67 PI was >10% in 11 of 22 cases (50%), with a
range of 10% to 90% (mean 32%, median 30%). The
presence of acute or chronic salpingitis did not
correlate with a high PI, as 7 of 11 tubes (64%) with
a high PI displayed acute and/or chronic salpingitis as
compared with 9 of 11 tubes (82%) with a low PI.
Among 8 with acute salpingitis, 5 (63%) had an
elevated PI as compared with 5 of 12 (42%) without
acute salpingitis (P = not significant).
DISCUSSION
PXS, also referred to as pseudoxanthomatous
salpingiosis, pigmentosis tubae, and melanosis tubae,
is an uncommon condition in which the lamina
propria of the fallopian tube contains pigment-laden
histiocytes. These are usually pseudoxanthoma cells,
but occasionally hemosiderin-laden macrophages
alone are seen. There are approximately 17 previously
reported individual patients (12–24) in addition to 2
Int J Gynecol Pathol Vol. 34, No. 3, May 2015
large series of unselected fallopian tubes, both
showing pigment deposition in 5% of cases (5,25).
This condition has most commonly been associated
with endometriosis which is found in the majority of
reported cases, but also occasionally with radiation
therapy (16). In this regard, it is noteworthy that the 2
patients in the current study who had a history of
radiation therapy for cervical carcinoma did not have
clinical or histologic evidence of endometriosis.
The pseudoxanthomatous pigment has been gen-
erally regarded as lipofuscin, has also been referred to
as ceroid, and is known to be positive for PAS and
Fontana-Masson stains. It has been studied ultra-
structurally in 2 reports (16,17). It is regarded as a
product of the phagocytic and metabolic breakdown
of hemosiderin within macrophages and accordingly,
iron staining is positive in a majority of cases (78% in
the current study). On the basis of its histology,
histochemistry, and ultrastructure, this pigment is a
form of lipofuscin. Although the term ‘‘ceroid’’ is
often used synonymously, ceroid is a family of
pigments found in a variety of pathologic conditions
and is not the same as lipofuscin (26).
Lipofuscin was first described by Hannover in
1842. It does not have a specific molecular formula,
but rather, has a highly variable composition. It is a
highly oxidized conglomerate of covalently cross-
linked proteins which comprise 30% to 70% of its
mass, and lipids which comprise 20% to 50% (26,27).
After the fifth decade, glycosylation is found. Iron
and other metals including copper, zinc, and alumi-
num comprise up to 2%. Lipofuscin is regarded as
one of the best known markers of aging, and
accordingly it has also been referred to as ‘‘age
pigment.’’ It accumulates predominantly in lyso-
somes, and some tissues accumulate large amounts
of lipofuscin that cannot be exocytosed or degraded.
There is some evidence that lipofuscin is not an inert
waste product, but may actively influence metabolic
pathways. Its ability to inhibit the degradation of
oxidized proteins contributes to its accumulation.
According to the ‘‘mitochondrial-lysosomal axis
theory of aging,’’ iron is a fundamental player, and
lipofuscin accumulation results from decreased deg-
radation of oxidized proteins and increased intra-
cellular free radicals. It has also been demonstrated
that lipofuscin formation is influenced by iron, and
that the free radical-producing ability of iron-loaded
lipofuscin is 4 times higher than that without iron
loading (27).
Although the role of iron in carcinogenesis is
complex and there are some conflicting data, it is
 PXS AS AN EX VIVO MODEL OF FALLOPIAN TUBE SEROUS CARCINOGENESIS
clear that iron acts as an initiator or a promotor of
carcinogenesis in a variety of human and animal
settings (5–10). There are several proposed mecha-
nisms of iron-induced tumor induction or promotion.
These include oxidative DNA damage by iron-
catalyzed free radical production, alterations in gene
expression consistent with increased iron require-
ments in proliferating cells, and decreased immune
surveillance (6–10). Other heavy metals, some present
in lipofuscin as noted earlier, may also play a role in
the fallopian tube as many of these are known
carcinogens. A recent epidemiological study found
the risk of fallopian tube carcinoma to be elevated in
certain occupational groups associated with exposure
to iron and other heavy metals (28). It is notable that,
although the fallopian tube is believed to be related
only to serous carcinogenesis, the endometriosis-
related neoplasms of the ovaries, namely endome-
trioid and clear cell carcinoma, may also have an
iron-related etiology as several investigators have
suggested that the presence of high levels of catalytic
iron in endometriotic cysts is related to oxidative
stress-induced carcinogenesis in that setting (29).
Interestingly, one of the major target genes involved
in iron overload-induced carcinogenesis, CDKN2A/
2B, is involved in the TP53 pathway which is known
to be important in serous carcinogenesis (1–3,30).
Several authors have pointed out that the term
PXS is inaccurate because it does not appear to be an
active inflammatory process inasmuch as pigmented
histiocytes simply accumulate as they do in endome-
triosis, a condition which is not generally regarded as
inflammatory. Accordingly, other terms including
pseudoxanthomatous salpingiosis, melanosis tubae,
and pigmentosis tubae have been proposed (12,14,16).
However, the current findings do suggest that a
majority of such cases do display plasma cells and/or
neutrophils, and if hydrosalpinx is included as
evidence of longstanding, chronic, or resolved sal-
pingitis, 86% of the current series does in fact display
evidence of salpingitis. As the term PXS is the most
common one in use, it appears reasonable to retain
this terminology, although pseudoxanthomatous
salpingiosis or melanosis tubae are acceptable alter-
natives. Melanosis tubae has the advantage of a
parallel with melanosis coli, a condition characterized
by the accumulation of similar pigment in the colonic
mucosa (12).
PXS is sometimes confused with xanthogranulom-
atous salpingitis, a similar condition in which the
tubal lamina propria is filled with foamy histiocytes.
The only morphologic difference is that in xanthog-
279
ranulomatous salpingitis, the histiocytes do not
contain pigment (20,22–24). This entity appears more
closely related to pelvic inflammatory disease than to
endometriosis. A few reported cases of xanthogranu-
lomatous salpingitis appear to be examples of
PXS (22,23).
Inflammation has long been thought to play an
important role in carcinogenesis in a variety of sites.
Until recently, ovulation-induced surface epithelial
damage and repair inducing an inflammatory micro-
environment was believed important in ovarian
carcinogenesis. Now with the shift in focus to the
fallopian tube, salpingitis is a new suspect. Several
investigators have demonstrated a positive correla-
tion of salpingitis with ovarian serous neoplasms (11).
Postulated mechanisms of inflammation-induced
carcinogenesis also involve the formation of free
radicals as does iron-induced carcinogenesis as noted
earlier, and conceivably both inflammation and free
radicals are important. In addition to the more
commonly cited mechanism of chronic inflammation-
induced free radical production, a recent review
suggests that in some settings, sustained oxidative
stress can lead to chronic inflammation, the reverse of
this process (31). A recent study showed that certain
inherited single-nucleotide polymorphisms in inflam-
mation-related genes influence ovarian carcinoma
risk (32).
We performed p53 and Ki67 stains to determine
whether the presence of iron had a detectable
influence on the tubal epithelium. We found p53
signatures in 9%, somewhat lower than the 19% to
33% seen in previously reported controls (33,34).
More interestingly, the Ki67 PI was elevated in half
the cases tested, with a mean of 32% in the most
actively proliferating areas. The significance of this
finding is unclear. It could be a reparative reaction to
inflammation; however, those tubes with elevated
proliferation indices were not more likely to harbor
inflammation. Whether iron exposure is related to
this finding is unknown.
In summary, this series characterizes the clinical
and pathologic features of PXS and confirms its close
association with endometriosis and occasional asso-
ciation with radiation. Whether past iron exposure or
the presence of iron or iron-related compounds in the
lamina propria damages tubal epithelial DNA or
creates a microenvironment that promotes carcino-
genesis is an intriguing question that awaits further
study. The presence of this known carcinogen in
fallopian tube tissue suggests a model in which early
events in tubal serous carcinogenesis can be studied in
Int J Gynecol Pathol Vol. 34, No. 3, May 2015
280 J.D. SEIDMAN AND R. WOODBURN
tissue readily available from surgical specimens. Even
if iron ultimately proves to be important in only a
minority of serous carcinomas, this can nonetheless
prove to be a useful ex vivo model in which our
understanding of tubal serous carcinogenesis can be
advanced. In an analogous manner in lung cancer,
although silica, arsenic, and asbestos are considered
etiologically important in only a minority of pulmo-
nary carcinomas, studies of these substances in the
lungs have provided important insight into pulmo-
nary carcinogenesis (35–37).
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