title page title: “metastasis of ovarian cancer to breast: the

TITLE PAGE
TITLE: “METASTASIS OF OVARIAN CANCER TO BREAST: THE IMPORTANCE OF
PATHOLOGIC FEATURES IN THE DIAGNOSIS OF RECURRENCES”
AUTHORS:
Lavinia Domenici MD, Federica Tomao PhD, Margherita Giorgini MD, Ilaria
Sabatucci MD, Vanessa Colagiovanni MD, Ludovico Muzii PhD, Pierluigi
Benedetti Panici PhD
AFFILIATION:
Department of Gynecologic, Obstetrics and Urologic Sciences - “Sapienza”
University of Rome, Rome, Italy
KEY WORDS: breast, metastasis, ovarian cancer
CORRESPONDING AUTHOR
Lavinia Domenici, MD
Dept of Gynecologic, Obstetrics and urologic Sciences
“Sapienza” University
Viale Del Policlinico 155
00161 Rome
Tel: +39-06-4940550; Fax: +39-06-49970355
Email: [email protected]
ABSTRACT
Metastasis of ovarian serous carcinoma to the breast and/or axillary lymph nodes is a rare event.
Nevertheless, its recognition and distinction from mammary carcinoma are of great clinical importance
because the treatment and prognosis differ significantly. We report a case of serous ovarian cancer
metastasing to the breast and to axillary lymph nodes.
Introduction
Ovarian serous carcinoma usually presents at an advanced stage, but with disease limited to the
peritoneal cavity in 85% of patients[1]. However, metastasis of ovarian cancer to the retroperitoneal
organs such as kidney or distant organ metastases such as brain have also been previously reported but
very few reports describe extra-abdominal lymph node involvement in this type of tumour. In
particular, metastases to the breast from ovarian tumours are extremely rare. Clinical studies have
shown that the incidence of metastases to the breast ranges from 0.5 to 1.2% [2,3]. We present a case of
metastatic carcinoma to the breast in a patient with a k nown history of ovarian cancer and a new breast
lump. Importantly, this case had histopathologic features that can be confused with ductal carcinoma in
situ.
Case Report
A 47-year-old female patient with past medical history of stage IIA serous ovarian carcinoma 9 months
after cytoreductive surgery and three lines of adjuvant chemotherapy (carboplatin AUC6 plus taxol 175
mg/mq every three weeks) presented to the clinic for regular follow-up visit. CA-125 levels were in the
normal range and she had no evidence of disease. On physical examination, a 2 cm diameter, nontender, round, firm, and fixed breast mass was found in superior inner quadrant of the left breast of the
patient. Patient was not aware of this mass. Left axilla examination was positive for two solid, fixed
and nodes.
On mammography, a mass of 1.8 cm was detected (Figures 1a). Sonogram of bilateral breasts was
performed which showed a 2.9 cm × 2.1 cm vascularized left breast mass (Figure 1b) and two
suspicious left axillary lymph nodes of 1.2 and 1.5 cm (Figure 1c).
A surgical excision of the mass was performed. Microscopic examination of the breast mass revealed a
ductal carcinoma in situ. Immunohistochemical studies showed that the tumo ur cells expressed
estrogen receptor (80%) and progesterone receptor (20%). There was no expression of HER-2/neu
oncoprotein. After three months a PET/CT scan showed progression of the disease with multiple
enlarged celiac, para-aortic, aorto-caval and axillary lymph nodes (SUV max 7.4). CA125 level was
41.5 U/ml at that time. She received a combination therapy of cisplatin (75 mg/m2, d1 of a 21-day
cycle) and gemcitabine (1000 mg/m2, on day 1 and 8 of a 21-day cycle). After three chemotherapy
cycles, a PET/CT showed a good response to chemotherapy. Surgery was planned and an elective
axillary clearance was undertaken. Thirteen lymph nodes were obtained from the axillary fat. Of the 13
axillary lymph nodes obtained, five showed metastatic deposits that were identical to the ovarian
primary. Immunohistochemical staining performed on the nodes was positive for WT-1, p16, and CA125 while cytokeratin 20 (CK20) and gross cystic disease fluid protein-15 (GCDFP-15) were negative.
According to microscopic and immunocytochemical findings, the origin of axillary lymph node
metastasis was ovarian cancer. An immunohystochemical review of the primary breast tumour and of
the ovaries previously removed, was performed. The analysis confirmed a metastasis of papillary
serous adenocarcinoma of the ovary on the breast tissue. The histomorphology of both tumors was
similar regarding cytological atypia, which showed high nuclear pleomorphism and many mitoses.
However, their growth patterns were different. The breast metastasis showed a predominantly solidnodular growth pattern, whereas the primary ovarian tumor, beneath solid sheets with slit- like spaces,
also contained small foci with a typical papillary growth pattern. The latter finally led to the diagnosis
of a primary serous ovarian cancer. In all the slides evaluated, the tumors showed the same
immunohistochemical profile: nearly all the tumor cells showed positive reactions for cytokeratins 5
and 6, which in general is not the case in invasive breast cancer, but is in ovarian cancer. CA 125 and
WT-1 were positive in both specimens. GCDFP-15 and cytokeratin 17 (CK17) showed negative
immunoreactions.
The summarized immunoprofile of both tumors strongly supported the
histomorphological diagnosis of ovarian serous cancer.
No additional surgical treatment was given to the patient. The patient has been still treated by nonpegylated liposomal doxorubicin (30 mg/m2, on day 1 of a 15-day cycle) for 3 months and has a stable
radiological and clinical response.
Discussion
Ovarian carcinoma is the second most common gynaecologic malignancy.[1] Papillary serous histology
accounts for as many as 75% of them [4]. Metastasis of ovarian serous carcinoma to the breast and
axillary lymph nodes is very rare [5,6], only few cases have been reported in the literature. Recine et al.
[5] reported a series of 18 cases of stage III-IV ovarian serous carcinoma, which had metastases to
breast four cases, in axillary lymph nodes in six cases or both in eight cases. The breast and/or axillary
lymph node metastases were discovered at an average of 30 months after presentation as in our case
(36 months).
When tumours in the breast or axillary lymph nodes are found before or simultaneously with an ovarian
carcinoma, diagnostic difficulties may arise. The use of immunohistochemical markers such as WT-1
and GCDFP-15 may aid in determining the origin of the tumour if an ovarian primary is considered.
This is important because the treatments of these two entities are different.
Furthermore, metastatic cancer to the breast from an ovarian primary is associated with a poor
prognosis, with a majority of patients dying within one year [6, 7]. Kayikcioglu et al. [8] presented the
case of a patient that was initially stage IIC epithelial ovarian cancer. After two years, she presented
with bilateral metastatic breast disease derived from the primary ovarian cancer. Although she was
heavily treated, she died 18 months after diagnosis. Breast metastases from ovarian cancer were found
an average of 2 years after initial diagnosis [9] and were usually associated with disseminated
disease. It is interesting that in our patients there was no evidence of disease outside breast.
Immunohistochemical markers may aid in determining the origin of bre ast or axillary lymph node
metastases. Yamamoto et al. [10] analysed WT-1 immunoreactivity in 119 patients with ovarian serous
cancer and showed that WT-1 positivity is positively correlated with high grade, advanced stage and
higher Ki-67 index, higher bcl-2 expression and poorer outcome in a study. Although WT-1 positivity
can be seen in many solid tumours, it has been identified as a possible marker mostly for ovarian
cancer.
We suggest that, in patients with history of ovarian cancer who present with axillary or breast mass,
every effort should be made to have an accurate histological diagnosis since this has a great impact on
treatment. It is critical to recognize histologic pattern and distinguish it from de novo ductal carcinoma
in situ. Immunohistochemistry is essential when the diagnosis is still vague.
CONSENT
Written informed consent was obtained from the patient for publication of this Case report and any
accompanying images. A copy of the written consent is available for review by the Editor of this
journal.
COMPETITING INTERESTS
All authors declare that they have no competing interests.
ACKNOWLEDGEMENTS
None.
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FIGURES
Figure 1 – A: Mediolateral oblique (MLO) vie w of a mammogram shows breast mass (red row)
B: Breast mass with smooth margin and homoge nous echotexture. Color Doppler reveals
irregularly branching neovascularity. C: Round hypoechoic lymph node with a diffusely
enlarged cortex is seen on US, and color Doppler US shows increased central flow.