Case 1 -
Tubal Intra-Epithelial Carcinoma, Metastatic to the Ovary (Fimbrial-Ovarian Carcinoma)
Brigham & Women’s Hospital
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The patient is a 78 year old woman with a history of invasive ductal breast carcinoma 5 years prior
with metastasis to the right clavicle 2 years later. She was in good health and undergoing routine
radiologic surveillance when a 3cm left adnexal mass was identified on PET/CT scan, and confirmed to be
cystic on ultrasound. Left salpingo-oophorectomy was performed, with omental and retroperitoneal lymph
node biopsies. Exam of the left adnexa revealed a grossly unremarkable fallopian tube and an adherent
ovarian mass. The omental and lymph node biopsies were negative. The uterus and right adnexa had been
removed previously, with a diagnosis of dermoid cyst. The section submitted is from the left ovarian
Case 1 - Slide 1
Case 1 - Figure 4
High power image of the ovarian tumor. Note the uniform pattern of supranuclear vacuoles.
Case 1 - Figure 5
High power image of the ovarian tumor. The cytoplasmic vacuoles were mucicarmine negative and very weakly positive for PAS.
Case 1 - Figure 6
CK7 immunostain is diffusely positive in this tumor, supporting a Mullerian origin.
Case 1 - Figure 7
CK20 immunostain is heterogenous, which does not support a colon primary but would not exclude an upper gastrointestinal or pancreatic primary.
Case 1 - Figure 8
CDX2 immunostain is heterogenous, which does not support a colon primary but would not exclude an upper gastrointestinal or pancreatic primary.
Case 1 - Figure 9
SMAD4 immunostain is positive. This is non-diagnostic for a metastatic tumor of the pancreas.
Case 1 - Figure 10
p16 immunostain is diffuse and strongly positive. This is unusual for a well differentiated endometrioid or mucinous carcinoma and suggests an unusual variant.
Case 1 - Figure 11
p53 immunostain is diffusely positive. This is unusual for a well differentiated endometrioid or mucinous carcinoma and suggests an unusual variant of non-serous Mullerian carcinoma.
The case in question raises the common dilemma of ascertaining the site of origin for a well
differentiated ovarian tumor that has abundant cytoplasmic vacuoles, reflecting a secretory or mucinous
product. The differential diagnosis in a case such as this includes the following:
Did this tumor arise in a remote, non-Mullerian
site? The presentation of this tumor, as a large, non-necrotic, well to
moderately-differentiated gland-forming, expansile mass with a smooth surface, does not strongly support
a metastasis from the gastro-intestinal tract. Nevertheless, immunostains for CK7, CK20, SMAD4 and CDX2
were ordered. The immunophenotype was as follows: CK7(+++), CK20(+), CDX2 (+) and SMAD4 (+++). Based
on this and the tumor morphology, a primary tumor arising in the gastrointestinal tract was considered
unlikely; a primary in the pancreatico-biliary tracts could not be excluded but a CT scan of that region
- A metastatic tumor from the gastrointestinal or pancreatico-biliary tracts
- A primary tumor of the ovary
- An implant or metastasis from another Mullerian site, such as the cervix, endometrium or fallopian tube
Did this tumor arise from the ovary or from another
Mullerian site? Four potential Mullerian primary sites must be considered in cases such as
this, and include the following:
Cervix: Approximately 5% of cervical adenocarcinomas will metastasize to the ovary, including
occasional tumors that have minimal or no histologic evidence of cervical stromal invasion. In our
experience, younger age (under 50 years of age), the presence of nuclear hyperchromasia exceeding that
typically seen in gland forming endometrioid carcinomas, apical eosinophilia and mitoses that appear
"suspended" in the apical cytoplasm, are helpful distinguishing features. Such tumors are typically HPV
positive and will immunostain strongly and diffusely for p16. However, p16
immunostaining is not specific for metastatic cervix carcinomas and although less diffuse in
endometrioid carcinomas, it will not distinguish these tumors from some upper genital tract
Endometrium: Approximately 12% of endometrioid carcinomas of the ovary are associated with a
synchronous endometrial primary; the proportion of well-differentiated endometrioid tumors of the ovary
that are metastases from the endometrium is very low.
Fallopian tube: There is increasing evidence that a subset of pelvic serous carcinomas
originate in the distal fallopian tube as a serous tubal intraepithelial carcinoma (STIC). Approximately
80% of pelvic serous carcinomas detected in risk-reducing salpingo-oophorectomies in women with BRCA1 or
BRCA2 mutations arise as STICs in or near the fimbria. The percentage of unselected (and advanced)
ovarian or peritoneal serous cancers that arise in the tube is less clear, but from 35-47% are associated
with a STIC. A precursor (the p53 signature) has been described in the fimbria and linked to STIC,
further implicating the salpinx in the genesis of many "ovarian" serous carcinomas. Perhaps relevant to
this case, early endometrioid carcinomas have been identified in the fimbria in association with similar
carcinomas in the ovary, implying a source in the tube.
The ovary: Unilateral carcinomas of the ovary, or those forming a dominant mass, support an
ovarian origin. In order of decreasing frequency, mucinous, endometrioid or serous can present as a
unilateral or unilaterally dominant mass.
Additional biomarker information and its significance in this case
p16: This tumor is strongly p16 immunopositive. This is consistent with either a metastasis
from a primary cervical tumor, an unusual variant of serous carcinoma or high grade endometrioid
HPV: This tumor was tested for HPV by PCR and scored negative. This is strong evidence
against a cervical primary.
P53: Although this tumor has prominent cytoplasmic vacuoles, the p53 immunostain is strongly
and diffusely positive. Based on what we know about the molecular pathways to mucinous and well
differentiated endometrioid carcinomas of the ovary, the presence of strong p53 immunostaining usually
excludes these tumor types. It does not exclude a colonic, gastric, lung or pancreatic primary, but
these are unlikely in view of the other findings. This leaves open the possibility of an unusual variant
of mullerian carcinoma in which the p53 immunophenotype is at odds with the histopathology.
Co-existing tubal intraepithelial carcinoma
Examination of the ipsilateral fallopian tube in this case revealed an unusual finding, which was an
intra-epithelial carcinoma with a focally secretory pattern (figure at right). Like the ovarian tumor,
the tubal lesion was diffusely positive for p16 and p53. There was no lamina propria invasion of the
Could both the ovary and tubal neoplasms represent metastases from another site, such as the
gastro-intestinal or pancreatico-biliary tracts?
Could both tumors signify separate primary neoplasms (ie a multi-focal carcinoma of the genital
- There is scant conclusive evidence in the literature of gastro-intestinal or pancreatic tumors metastasizing to the mucosal surface of the fallopian tube.
Is it possible that a primary gynecologic tumor has metastasized to the fallopian tube (ie from
ovary to fimbria, not the reverse)?
- Separate primary neoplasms of the tube have been reported in cases of endometriod carcinoma of the endometrium.
- Rare examples of multifocal mucinous tumors of the cervix, endometrium, tube and ovary have been reported, but there is no molecular evidence confirming that these are indeed separate primaries.
- P53 mutation analysis of paired STICs and remote serous tumors in the ovary or peritoneum has invariably confirmed identical p53 mutations, consistent with a single source for both tumors.
A non-serous immunophenotype
- Although serous carcinomas frequently metastasize to the serosal surface of the tubes, there is no conclusive evidence that they implant and spread along the tubal epithelium. Nevertheless, this is a possibility, particularly in advanced carcinomas.
- Studies of early carcinomas arising in BRCA+ women suggest the opposite is usually the case due to the fact that a high proportion emerge in the fimbria rather than ovarian surface or ovarian cortical inclusions..
- The tumor is negative (or very focally positive) for WT-1 and PAX 8, excluding a conventional serous carcinoma.
- The tumor is muci-carmine negative, and weakly PAS and PAS-D positive.
Tubal intra-epithelial carcinoma, metastatic to the ovary (Fimbrial-ovarian
This case is unusual because of the following:
- The tumor forms uniform (grade 1) glands with grade 2 nuclear features.
- It is strongly p53 positive, highlighting a disparity between glandular differentiation and p53 immunophenotype
- Despite the presence of p53, it is WT-1 and PAX8 negative, consistent with a non-serous lineage.
- Armes JE, Lourie R, de Silva M, Stamaratis G, Boyd A, Kumar B, Price G, Hyde S, Allen D, Grant P,
Venter DJ. Abnormalities of the RB1 pathway in ovarian serous papillary carcinoma as determined by
overexpression of the p16(INK4A) protein.
Int J Gynecol Pathol. 2005;24:363-8.
- Jarboe E, Folkins A, Nucci MR, Kindelberger D, Drapkin R, Miron A, Lee Y, Crum CP.
Serous carcinogenesis in the fallopian tube: a descriptive classification. Int J Gynecol Pathol.
- Kindelberger DW, Lee Y, Miron A, Hirsch MS, Feltmate C, Medeiros F, Callahan MJ, Garner EO, Gordon RW,
Birch C, Berkowitz RS, Muto MG, Crum CP Intraepithelial carcinoma of the fimbria and pelvic serous
carcinoma: Evidence for a causal relationship.
Am J Surg Pathol. 2007;31:161-9
- Lee KR, Young RH. The distinction between primary and metastatic mucinous carcinomas of the ovary:
gross and histologic findings in 50 cases. Am J Surg Pathol. 2003;27:281-92.
- Lee Y, Miron A, Drapkin R, Nucci MR, Medeiros F, Saleemuddin A, Garber J, Birch C, Mou H, Gordon RW,
Cramer DW, McKeon FD, Crum CP. A candidate precursor to serous carcinoma that originates in the distal
fallopian tube. J Pathol. 2007 Jan;211(1):26-35. Erratum in: J Pathol. 2007;213:116
- 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. 2006 ;30:230-6.
- Roh MH, Kindelberger D, Crum CP. Serous Tubal Intraepithelial Carcinoma and the Dominant Ovarian
Mass: Clues to Serous Tumor Origin? Am J Surg Pathol. 2008 Nov 13
- Ronnett BM, Yemelyanova AV, Vang R, Gilks CB, Miller D, Gravitt PE, Kurman RJ.
Endocervical adenocarcinomas with ovarian metastases: analysis of 29 cases with emphasis on minimally
invasive cervical tumors and the ability of the metastases to simulate primary ovarian neoplasms. Am J
Surg Pathol. 2008;32:1835-53
- Seidman JD, Kurman RJ, Ronnett BM. Primary and metastatic mucinous adenocarcinomas in the ovaries:
incidence in routine practice with a new approach to improve intraoperative diagnosis. Am J Surg Pathol.
- Vang R, Gown AM, Farinola M, Barry TS, Wheeler DT, Yemelyanova A, Seidman JD, Judson K, Ronnett BM.
p16 expression in primary ovarian mucinous and endometrioid tumors and metastatic adenocarcinomas in the
ovary: utility for identification of metastatic HPV-related endocervical adenocarcinomas. Am J Surg