Case 5 -
Metastatic Serous Carcinoma Arising in the Tubal Fimbria
Christopher P. Crum
Brigham & Women’s Hospital
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A 60-year old woman presented with a history of pelvic discomfort. Physical exam
disclosed a large pelvic-abdominal mass. Laparotomy was performed, with bilateral salpingo-oophorectomy,
segmental bowel resection, omentectomy and subtotal removal of the tumor.
Metastatic Serous Carcinoma Arising in the Tubal Fimbria
This case is relatively straightforward, and is presented because it is emblematic of the
paradigm shift that is currently taking place with regard to the perceived origin of surface ovarian
cancer. This is a consequence of several studies that have continually questioned the time-honored
notion that most ovarian serous carcinomas are derived from the ovarian surface epithelium or cortical
inclusions. While this pathway is clearly the most plausible for endometrioid and mucinous tumors,
high-grade serous carcinomas have rarely been demonstrated to arise on the ovarian surface or within
Moreover, recent studies have shown that most early cancers detected in BRCA+ women occur in the
fallopian tube, specifically in the distal segment
Recently, we discovered that by carefully examining the entire tube, including the fimbria, in
salpingooophorectomy specimens from women with ovarian cancer, we could detect early (intraepithelial)
carcinomas in a substantial proportion of cases in which the bulk of the tumor was present on the ovaries
or pelvic surfaces . This has provided further support
to a wide range of pre-existing data that suggested the tube as an important source of pelvic serous
For those who must evaluate prophylactic salpingooophorectomy specimens from ovarian cancer-prone
populations, two additional tools are helpful, including the method of sectioning and the use of
biomarkers in resolving problematic cases. The first is a protocol to maximize the proportion of the
fallopian tube mucosa that is accessible for microscopic examination. In this protocol, which includes
sectioning and extensively examining the fimbriated end (SEE-FIM), the tubes are sectioned in-toto. The
ampullary portion is sectioned at 2-3 mm intervals and the infundibulum is amputated and sectioned
longitudinally to maximize exposure of the fimbrial mucosa .
This increases the longitudinal surface area of the fimbria that is examined by approximately
60%. In a small series of cases of serous carcinomas detected in the tube in BRCA+ women, three of four
were identified in the fimbria and in two, the area involved amounted to one or two discrete foci in
individual plicae. Although the fimbria has not been established as the dominant site for early tubal
carcinoma, this protocol provides for a more systematic view of this area.
The second variable is immunostaining for both p53 and MIB-1. In a recent study, we found that
virtually all serous carcinomas of the fallopian tube were intensely p53 positive, presumably due to
mutations in the p53 tumor suppressor gene that retard degradation of the protein product. iv
However, because p53 immunostaining can occur in non-neoplastic epithelium, a second marker was necessary
to increase the specificity for serous carcinoma. support the diagnosis of neoplasia in this setting.
Immunostaining for MIB-1 was helpful in this context, because it identified proliferating cells. The
combination of a high index (70-80% in at least a portion of the epithelial cells) of both MIB-1 and p53
in the same epithelial focus correlated strongly with cytologic atypia and the diagnosis of serous
With the combination of the above biomarkers and histopathology, it is possible to identify three
different and overlapping subsets of early serous neoplasia. Whether these comprise stages of the same
process is difficult to determine in all cases, but the juxtaposition of these entities suggests that
they merit consideration. They are as follows:
Group I consists of cohesive pseudo-stratified epithelia with absence of cilia and a
high MIB-1 and p53 staining index. The epithelia display a variable loss of normal cell
polarity and focal nuclear enlargement.
Group II display a prominent stratified epithelium with a greater loss of cell
polarity. The atypia may or may not be more conspicuous but is accompanied by irregular thickness and
loss of cohesion with small linear fractures in the epithelial cell mass.
Group III consists of highly disorganized and un-polarized clusters of malignant
tumor cells with marked atypia. These tumor cells are frequently seen attached to the tubal mucosa in
cases of advanced carcinoma. They are frequently multi-focal and similar to invasive tumor elsewhere in
the specimen. In contrast to Groups I and II, tumor cells in Group III while technically
"intraepithelial", cannot be readily distinguished from serous carcinoma growing on serosal surfaces .
Beyond the diagnostic exercise of locating early cancers in the fallopian tubes of prophylactic
salpingo-oophorectomies, the more compelling issue emerges, which is the significance of the fallopian
tube in the pathogenesis of pelvic serous carcinoma. If the most recent studies are confirmed, the
fallopian tube will become the target for studies of both pathogenesis and prevention of this disease.
Practicing pathologists can resolve this at the level of their practice(s) by carefully examining the
distal fallopian tube in cases of "ovarian" serous carcinoma.
The fact that most fallopian tube carcinomas originate in the distal portion explains the paradox of
why ovarian serous carcinoma traditionally been more common than its tubal counterpart. Most serous
carcinomas of the tube arise near the fimbria, gain access to the pelvic cavity, and frequently present
with ovarian surface and/or peritoneal involvement that exceeds in bulk that found in the tube.
Moreover, some of these tumors can spread when very small and would not be appreciated on a cursory exam
of the salpinx. In this setting these tumors have often been interpreted as ovarian or peritoneal in
origin, as evidenced by this case presentation. Conversely, central tubal carcinomas are uncommon, yet
are the most likely to present with a dominant tumor mass in the tube. This explains the perceived
rarity of tubal carcinoma in the past, a perception that will change with closer attention to the distal
fallopian tube in cases of "ovarian" cancer.
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- Medeiros F, Muto MG, Lee Y, Elvin JA, Callahan MJ, Feltmate C, Garber JE, Cramer DW, Crum CP. The Tubal Fimbria is a Preferred Site for Early Adenocarcinoma in Women with Familial Ovarian Cancer Syndrome. Am J Surg Pathol, 2005, in press
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- Kindelberger D, Lee Y, Hirsch MS, et al. Evidence that surface ovarian carcinomas originate in the distal fallopian tube. Submitted for publication
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- Chang P, Crum CP. The fallopian tube, in Crum CP and Lee KR, eds. Diagnostic Gynecologic and Obstetric Pathology. WB Saunders Elsevier, 2006
- Lee Y, Medeiros F, Kindelberger D, Callahan M, Muto M, Crum CP. Advances in the Recognition of Tubal Intraepithelial Carcinoma (TIC): Applications to Cancer Screening and the Pathogenesis of Ovarian Cancer. Adv Anat Pathol , 2006 (in press)