Invasive Micropapillary Carcinoma of the Breast

Guido Pettinato, MD; Carlos J. Manivel, MD; Luigi Panico, MD; Lucianna Sparano, MD; Giuseppe Petrella, MD


Am J Clin Pathol. 2004;121(6) 

In This Article


Breast cancer is a heterogeneous disease, and extensive efforts have been made to enhance our understanding of its biology to enable us to identify potentially aggressive tumors and patients at higher risk for recurrence and metastasis. This information might be useful in planning appropriate therapeutic regimens. Increased recognition of specific subtypes logically has decreased the number of cases placed in the category of infiltrating ductal carcinoma, not otherwise specified. Studies have demonstrated remarkable correlation of each histologic subtype with its biologic behavior, as some phenotypes are recognized to be more aggressive and to be associated with short-term treatment failure.[3,4]

In 1991, attention was drawn to a morphologically distinctive and clinically aggressive variant of invasive ductal carcinoma of the breast not previously identified, in a series of 37 patients.[5] This tumor was characterized by delicate pseudopapillary structures lacking fibrovascular cores floating freely in empty, clear spaces formed by a stromal, fibrocollagenous, sponge-like network mimicking extensive lymphatic permeation. Other relevant aspects of the tumor were tubuloalveolar structures with a central lumen, the high-grade atypia of the tumor cells, the unusually high frequency of psammoma bodies, and a high incidence of true lymphatic invasion. We were struck by the histologic similarity of this tumor to the serous papillary carcinomas of the ovary and the endometrium[21]; the latter also are associated with a surprisingly high frequency of abdominal lymph node metastases and aggressive clinical course. We called this particular variant pseudopapillary (serous-like) carcinoma of the breast, recognizing that the neoplastic tufts were distinctively devoid of fibrovascular cores.

We have identified 62 cases of this rare and distinctive variant of breast carcinoma; the clinicopathologic observations of the present study confirm our initial views.

During the past few years, series illustrating this variant of breast cancer have been published,[6,7,8,9,10,11,12,13,14,15] and aspiration cytology features in single case reports or small series have been illustrated.[20,22,23,24,25,26,27,28,29] ( Table 3 ) summarizes the relevant clinical and pathologic findings reported in a total of 269 cases, included the present series. We did not include the recent series of Nassar et al[15] because in the majority of their cases (79%), the micropapillary pattern constituted only a minor proportion of the tumor volume.

In the 269 reported cases, the age range at diagnosis was 25 to 92 years (mean, 55.5 years). The majority of patients had a palpable mass, but occasionally, a routine mammogram detected the lesion as a result of microcalcifications or as a soft tissue density. Laterality and location of tumors in the breast did not differ from ordinary invasive ductal carcinomas. Tumor size ranged from 0.1 to 10 cm (median, 2.6 cm). In a recent series, 25% of the tumors were 1 cm or smaller, and 16% were 0.5 cm or smaller.[14]

The gross appearance is not specific and is similar to that of ordinary ductal carcinomas. All authors have described the pseudopapillary and tubuloalveolar arrangement of tumor cell clusters in sponge-like, clear empty spaces, mimicking extensive lymphatic invasion; the same pattern of growth has been observed in dermal lymphatics, chest wall recurrences, and lymph node metastases. Histologic grading has been evaluated as prevalent grade 2 in 2 series,[10,13] ranging from 50% to 64% (mean, 57%), and prevalent grade 3 in 4 other studies,[11,12,14] including the present series, ranging from 60% to 87% (mean, 70.2%). Unusually frequent lymphatic vessel invasion has been observed (57.8% of the tumors [range, 33%-71%]); lymphatic permeation frequently was massive. Almost 80% of the patients had axillary lymph node metastases; the incidence varied from 44% to 100%. Often more than 3 lymph nodes were affected. These features corroborate the strong lymphotropic, metastasizing phenotype of this variant of breast cancer.

In an earlier study,[5] some prognostic parameters in these tumors were compared with those of 100 consecutive cases of ordinary infiltrating ductal carcinoma. In invasive pseudopapillary carcinomas, there was a statistically significant higher incidence of nodal metastases (92% vs 62%), N2 (TNM classification, 30% vs 6%), lymphatic vessel invasion (38% vs 12%), perineurial infiltration (52% vs 5%), dermal lymphatic invasion (16.5% vs 2%), and nipple invasion (60% vs 22%).

An unusual number of psammoma bodies was found in association with this tumor; the incidence ranged from 47% to 62%. It has been suggested that the lack of fibrovascular cores and subsequent ischemic cell degeneration might be responsible for the formation of concentric calcifications[10]; however, frank necrosis is rare. The similarity of this variant of breast cancer to the serous papillary carcinoma of the ovary and endometrium has raised the need to distinguish this tumor from metastases of müllerian tumors.[6,8,10] Appropriate clinical information and the presence of an intraductal component are important clues for this differential diagnosis.

A variant of transitional cell carcinoma of the bladder designated micropapillary carcinoma has been described.[30,31,32] These tumors are characterized by infiltrating tight clusters of micropapillary aggregates that grow within empty spaces, mimicking vascular invasion. The authors have drawn attention to the possibility of confusing this tumor with a metastatic serous papillary carcinoma of the ovary. Interestingly, this micropapillary variant of bladder cancer is associated with high-grade, high-stage, massive lymphatic invasion and a poor prognosis. Recently, a micropapillary component ranging from focal to prominent was described in adenocarcinoma of the lung.[33] The authors believe that this component might be more likely to metastasize.

The description of this peculiar pattern of growth in carcinomas of different origin with a common aggressive behavior is an argument against the likelihood that the pattern might be the result of tissue artifact. Furthermore, the occurrence of the same pattern in recurrences and metastases and the presence of synchronous ordinary invasive ductal carcinoma in bilateral cases also point against tissue artifact. Finally, an additional argument against this hypothesis is offered by a cell line obtained from the fine-needle aspiration material of 1 case[34]; the morphologic characteristics of the original tumor were retained in the cell culture, with pseudotubular and micropapillary clusters devoid of connective axis. Yet, tumor cells showed high-grade nuclear features, overexpressed HER2/neu, and were negative for steroid receptors.

The particular architecture of micropapillary carcinoma of the breast has been attributed to a rotation of cell polarization, described by Petersen[7] as an inside-out growth pattern. Tumor cells often show a well-defined apical pole oriented toward the stroma. The inversion of cell polarization has been confirmed by the ultrastructural study of 2 cases that showed external cellular surfaces covered by microvilli directed toward the surrounding stroma.[8] In our cases, we have found aspects that reflect this abnormal cell polarization and that might be correlated with the characteristic invasiveness of the tumor. An inverted membrane cytoplasmic immunoreactivity for MUC1 toward the stroma and not in the luminal cytoplasm was present in the majority of the cases, often associated with high cytoplasmic staining in the most pleomorphic tumors.

MUC1 is a mucin expressed on the apical surface of breast epithelial cells. In breast carcinoma, MUC1 expression is variable in amount and cellular localization, the significance of which is controversial. However, aberrantly localized MUC1 in the cytoplasm or nonapical membrane of tumor cells is associated with a worse prognosis.[35]

We also found a characteristic absence of expression of E-cadherin in the cytoplasmic membrane toward the fibrocollagenous stroma. Cadherins are transmembrane glycoproteins that mediate calcium-dependent intercellular adhesion and are involved specifically in epithelial cell-to-cell interactions.[36] Evidence exists to indicate that down-regulation of cadherin expression and/or function is an important factor in the malignant progression of epithelial tumors.[37] In the breast, E-cadherin is thought to act as a metastatic or invasion suppressor gene, and the reduced expression of this adhesion molecule in breast carcinomas is associated with the acquisition of increased invasiveness and high metastatic potential.[38,39] The absence of expression of E-cadherin at the interface between the cytoplasmic membrane of tumor cells and the stroma might represent one of the abnormalities underlying inversion of cell polarization that characterizes invasive micropapillary carcinoma of the breast.

Other biologic characteristics of this tumor have been evaluated in 5 studies.[10,11,12,13,14] The expression of proto-oncogene HER2/neu is increased in these tumors (74.2%). It is well known that this expression in patients with metastatic axillary nodes is associated with a high incidence of recurrence and short-term treatment failure.[40] Conversely, estrogen and progesterone receptors, which are directly related to the degree of cell differentiation in breast carcinomas, were positive in 56.8% and 39.7% of the cases, respectively. In this regard, whereas some authors have reported a high percentage of steroid receptor positivity,[13,14] others have found only a minority of tumors immunoreactive for these markers[10] (also in the present series). Proliferative activity, evaluated with MIB-1 in 130 cases, was considered significantly high in 87.6% of the tumors. Luna-Moré et al[13] found positivity for bcl-2 in 66% of the cases; this correlated with hormone receptor status. DNA ploidy was studied in 47 tumors in 2 series (Tresserra et al[11] and the present series); aneuploidy was found in 89% (n = 42) of the cases.

Tumor suppressor gene product p53, also associated with early recurrence and decreased survival in patients with advanced stage breast cancer,[41] was immunoreactive in 52.5% of the tumors. By using microdissection and polymerase chain reaction techniques, Middleton et al[10] showed loss of heterozygosity in locus 17p13.1 (p53) in 4 of 5 cases of invasive micropapillary carcinoma of the breast, with 80% concordance between molecular and immunohistochemical analyses. More recently, Thor et al,[42] using comparative genomic hybridization analysis in 16 cases of micropapillary carcinoma of the breast, demonstrated uniformity of chromosome 8p loss and other chromosomal gains and losses. These alterations were much more frequent in the micropapillary subtype than in other invasive breast cancer subtypes with HER2/neu immunopositivity. These data suggest that chromosome 8 might contain 1 or more genes whose loss leads to the inversion of polarity of tumor cells, the particular histologic features, and the lymphotropic phenotype associated with this histopathologic pattern. The expression of unfavorable prognostic markers is in accord with the advanced stage at diagnosis, even when the primary tumor is small. In the series by Walsh and Bleiweiss,[14] 64.3% of tumors 1 cm or smaller and 75% of tumors 0.5 cm or smaller had positive axillary lymph nodes.

Adequate follow-up data were available for 125 patients ( Table 2 ). This variant of breast carcinoma shows a high relapse rate and short disease-free interval. In fact, early local recurrence in the skin or chest wall occurred in each series. One study did not address recurrences.[13] There were 43 recurrences (61%) in 71 patients followed up from 2 months to 60 months after surgery (mean time to recurrence, 22.7 months). There were no significant differences between patients who underwent mastectomy and patients who underwent conservative surgery and radiotherapy. Follow-up in 1 series was limited to 24 months[11]; long-term follow-up (up to 14.5 years) was obtained for 110 patients. Forty-five of 105 patients died of disease, usually with widespread metastases, for a death rate of 42.9%. However, compared with patients with ordinary invasive ductal carcinoma with equivalent numbers of lymph node metastases, patients with invasive micropapillary carcinoma have similar survival rates.[12]

These results suggest that invasive micropapillary carcinoma of the breast is a distinct and aggressive variant of breast cancer with marked lymphotropism, extensive axillary lymph node involvement, frequent local recurrence, and distant metastases. This behavior seems independent of patient age, tumor size, location, histologic grade, and extent of the micropapillary growth pattern. More than once we have seen a pure pseudopapillary appearance in the lymph node metastases of tumors in which this pattern of growth was present in only 10% of the primary tumor. These morphologically adverse prognostic factors are supported by a number of biologically unfavorable prognostic markers such as high expression of the oncogenes HER2/neu and p53, a high proliferation index, aneuploidy, low expression of steroid receptors, aberrant mucin expression, and down-regulation of adhesion molecules.

The recognition of a micropapillary growth pattern in carcinoma of the breast is important because of its acquisition of increased lymphotropic phenotype and its association with high-stage disease. Aggressive neoadjuvant chemotherapy before surgery should be evaluated in these patients.