—  SPECIALTY CONFERENCE  —

Breast Pathology

Case 2 - Bilateral Metastatic Ovarian Papillary Serous Carcinoma

J. Jordi Rowe
Cleveland Clinic
Cleveland, OH





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Clinical History
A 44 year old woman underwent a mammogram for a palpable breast mass. In the right breast a mass is identified at 1 o'clock which corresponds to the palpable mass. In the left breast a mass is identified at 10 o'clock. No other masses or calcifications are seen in either breast. The patient underwent bilateral ultrasound guided needle core biopsies. The following images are representative of both masses.


Case 2 - Figure 1
Increasing magnifications of the tumor (4x, 10x, 40x). Note the clear spaces around the tumor nests, the nuclear grade, and the lack of tubular/alveolar pattern.
Case 2 - Figure 2
Increasing magnifications of the tumor (4x, 10x, 40x). Note the clear spaces around the tumor nests, the nuclear grade, and the lack of tubular/alveolar pattern.
Case 2 - Figure 3
Increasing magnifications of the tumor (4x, 10x, 40x). Note the clear spaces around the tumor nests, the nuclear grade, and the lack of tubular/alveolar pattern.
Case 2 - Figure 4
Lymphovascular invasion, 40x.

Case 2 - Figure 5
Estrogen receptor.
Case 2 - Figure 6
EMA staining pattern in invasive micropapillary carcinoma, 20x.
Case 2 - Figure 7
EMA staining pattern in ovarian papillary serous carcinoma, 20x.
Case 2 - Figure 8
GCDFP-15 staining pattern in ovarian papillary serous carcinoma, 20x.

Case 2 - Figure 9
PAX-2 staining pattern in ovarian papillary serous carcinoma, 20x.
Case 2 - Figure 10
WT-1 staining pattern in ovarian papillary serous carcinoma, 20x.

Pathological/Microscopic Findings and any Immunohistochemical or Other Studies:
The needle core biopsy demonstrates an infiltrative lesion obliterating the normal architecture of the breast. The tumor is composed of small nests of cells with a moderate nuclear to cytoplasmic ratio, and medium to large irregular nuclei with large nucleoli. Scattered evidence of single cell necrosis is seen. The infiltrative pattern is characteristic in that there is a clear space surrounding the nests of cells. No fibrovascular cores are identified within the tumor clusters. Lymphovascular invasion is present. Immunostaining for estrogen receptor is positive with 80% of the nuclei staining with a weak to moderate intensity.

Differential Diagnoses:
Invasive micropapillary carcinoma of the breast

Metastatic ovarian papillary serous carcinoma

Final Diagnosis:
Bilateral metastatic ovarian papillary serous carcinoma

Case Discussion:
The case presents and interesting issue; making a diagnosis of metastatic tumor needs to be considered in order to be appropriately diagnosed. Discernment between metastatic ovarian papillary serous carcinoma can be approached systematically. Once the hallmark pattern of 'retraction artifact' and inside-out architecture has been identified, the pathologist needs only to remember a small checklist prior to rendering a diagnosis. Is there a prior history of ovarian carcinoma? Is there a more recognizable invasive ductal or mucinous carcinoma component? Is there a clear DCIS component of micropapillary or cribriform subtypes? If yes to the latter two questions, then the likelihood that the tumor represents a metastasis is unlikely. If the patient has a prior history of ovarian carcinoma, then the likelihood of a metastasis is greater, and comparison of the ovarian primary to the current material is warranted. Unfortunately, ovarian papillary serous carcinoma has been known to metastasize bilaterally to the breasts, thus a bilateral synchronous tumor does not immediately exclude a metastasis. Morphology If the tumor in question is pure 'micropapillary' in morphology and pattern, analysis of the tumor cell morphology is valuable. Metastatic ovarian papillary serous carcinomas to the breast tend to have a greater N/C ratio, and larger more pleomorphic nuclei; in essence, grade 3 or high grade nuclei. The nuclei of invasive micropapillary carcinoma of the breast vary from low to intermediate grade. Invasive micropapillary carcinoma of the breast lacks fibrovascular cores, while they can be frequently seen in ovarian papillary serous tumors. More valuable yet, micropapillary carcinoma of the breast has a secondary morphologic pattern, the tubular/alveolar pattern, not seen in ovarian metastases. In addition, the single cell necrosis seen within our case of metastatic ovarian carcinoma is not a frequent finding in primary breast cancer of micropapillary subtype. Psammomatous calcifications are known to be associated with ovarian tumors and can be seen in their metastatic counterparts; yet, they are lacking in invasive micropapillary carcinoma of the breast. Lymphovascular invasion is a feature of both micropapillary carcinoma of the breast and ovarian papillary serous carcinoma. Immunohistochemistry A variety of immunohistochemical stains are available to aid in elucidating the correct diagnosis in this differential. Immunomarkers GCDFP-15 and mammaglobin are positive in breast primaries, approximately 35% and 55% of the time respectively. EMA is useful, as it can help identify invasive micropapillary carcinoma from metastatic papillary serous by the staining pattern. EMA stains around the outside of the glands in an inside out pattern in micropapillary carcinoma of the breast, while papillary serous carcinoma of the ovary has uniform strong cytoplasmic staining. WT-1 is positive in ovarian papillary serous carcinomas 78 % of the time; however, there is a pitfall. Primary breast micropapillary carcinomas are positive for WT-1 in 3-25% of cases, lowering the diagnostic utility of this marker. Recently, PAX-2 has been identified as a sensitive marker of metastatic ovarian serous papillary carcinomas (100% of cases stained positive), and is useful in this differential, as it is negative in breast invasive micropapillary carcinoma (0% of cases stained positive). The favored immunohistochemical stains that many pathologists think of as breast markers are not as helpful and may complicate a case unnecessarily. Estrogen receptor and progesterone receptor are 97% and 86% positive in ovarian papillary serous carcinoma and approximately 75% and 45% positive respectively in invasive micropapillary carcinoma of the breast. While expression of HER2 protein is seen in both ovarian and invasive micropapillary carcinomas of the breast, overexpression is limited to the latter.

Conclusion(s):
The most important step in not misdiagnosing metastatic ovarian papillary serous carcinoma as invasive micropapillary carcinoma of the breast is to recognize their overlapping histomorphologies. Other helpful features include the association of invasive micropapillary carcinoma with ductal carcinoma in situ, and unless the invasive component is pure micropapillary, it's additional association with invasive ductal carcinoma, NOS. Immunohistochemistry can be extremely useful is discerning between these two diagnoses, if used appropriately. PAX-2, and WT-1 are positive markers in ovarian papillary serous carcinoma, while EMA, GCDFP-15 and mammaglobin, if positive and appropriately interpreted, are helpful in diagnosing invasive micropapillary carcinoma of the breast. Estrogen and progesterone receptor analysis including HER2, are not specific and cannot aid in deciding a primary location.

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