Invasive Micropapillary Carcinoma
Invasive micropapillary carcinoma (IMPC) is a special type of invasive breast carcinoma (IBC) characterized by cancer cells with eosinophilic or granular cytoplasm, forming morule-like clusters, surrounded by clear stromal spaces. Tumor cells have characteristic reverse polarity, also known as an “inside-out” growth pattern: the apical pole of tumor cells faces the empty stromal spaces.
Incidence: Pure IMPC is a rare subtype of invasive breast cancer, accounting in its pure form for 0.9–2% of IBCs. The reported incidence of IBC with a micropapillary component is up to 8%.
Age: The reported median age of IMPC is from 48 to 62 years, consistent with that of patients with estrogen receptor (ER) positive IBC.
Sex: IMPC usually affects women, but single cases of male IMPC had been reported. In studies on male breast cancer, the reported incidence of IBC with micropapillary features varies between 0% and 11%.
Site: No specific site within the breast parenchyma was identified for these tumors.
Treatment: Currently stage I and II tumors are treated as IBC of no special type (IBC NST); however there are some suggestions that modification of current locoregional treatment would be beneficial in cases of IMPC: wider surgical margins and more aggressive axillary and supraclavicular management would enhance local disease control (Yu et al. 2015).
Outcome: Since the incidence of IMPC is low, studies on its outcome are sparse. It seems that despite the reported unfavorable tumor characteristics of IMPC (higher nuclear grade, frequent lymphovascular invasion (LVI), lymph node metastases (LNM), and extracapsular spread) (Chen et al. 2014; Yu et al. 2015) the overall prognosis of IMPC patients in multivariate analysis – when stratified for number of positive lymph nodes and other prognostic factors – is comparable to that of IBC NST patients (Yu et al. 2015). According to Chen’s study of 624 patients with IMPC, the prognosis is poor if the tumor is ER negative.
IMPCs do not have any particular features on grossing. The reported mean tumor size is between 1.5 cm and 3.9 cm, not significantly different from that of IBC NST (Yi-Ling et al. 2016).
The tumor cells of IMPC usually have eosinophilic cytoplasm, and they demonstrate a characteristic reverse polarity (“inside-out” pattern): the apical surface of the cells facing the empty stromal spaces and not the central pseudolumen, if present. In some cases apocrine features can be identified. True tubule formation is lacking; nuclear pleomorphism is only rarely pronounced. Number of mitoses is usually low to moderate. Most IMPCs are grade 2 or 3 lesions. Necrosis, tumor infiltrating lymphocytes (TILs) are not common.
Peritumoral LVI is detected in up to 70% of IMPC cases, while the LVI rate of IBC NST cases is 20% (Gruel 2014). It seems that neither the tumor size alone nor the extent of the micropapillary component but the presence of the micropapillary pattern correlates with the aggressive locoregional presentation of the tumor (Yi-Ling et al. 2016).
The majority of patients – up to 84% – present with axillary LNM at initial diagnosis. This rate is significantly higher than that of IBC NST patients with LNM, and the number of lymph nodes involved by metastatic disease is also higher in IMPC than in IBC NST cases.
Associated intraductal carcinoma (DCIS) is usually of micropapillary architecture with high-grade nuclei. Necrosis and microcalcifications may also be present.
IMPC is frequently positive for ER (66–94%) and progesterone receptor (PR) (50–84%). The prognosis of ER-negative IMPCs is usually poor. In reported series to date, basal cytokeratins are not expressed in IMPCs. Pure IMPCs are likely to have high Ki67 index, and cyclin D1 is also highly expressed (Marchiò et al. 2008).
The reported incidence of HER2-positive IMPC is inconsistent, which varies between 8.3% and 95% (Yi-Ling et al. 2016). The American Society of Clinical Oncology (ASCO) and the College of American Pathologists (CAP) 2013 guidelines for HER2 testing suggest that micropapillary carcinoma with HER2 immunohistochemistry staining that is intense but incomplete (basolateral or U-shaped) and therefore would be considered score 1+ may actually be amplified by fluorescent in situ hybridization (FISH). Thus the guideline recommends that these IMPC cases should be reported as equivocal (score 2+), and alternative testing should be carried out. This recommendation of the 2013 ASCO/CAP guideline was based solely on the results of a single study, which was reinforced later by others.
Genetic heterogeneity is a characteristic feature of IMPCs. Some cases show duplication or deletion of long segments of a few chromosomes, or multiple segments of duplications and deletions may be present throughout the whole genome, or multiple amplicons on single chromosome arms may be identified (Marchiò et al. 2008).
Microarray-based comparative genomic hybridization studies demonstrated that pure IMPCs and IBC NST cases with micropapillary features are remarkably similar and harbor genetic alterations distinct from that of grade- and ER-matched cases of IBC NST. Recurrent gains in regions of 8p, 8q, 17q, and 20q, while losses of 1p, 8p, 13q, and 20q, were more prevalent in IMPC than in IBC NST (Marchiò et al. 2009; Li et al. 2012; Wang et al. 2015).
The genes SEC63 and FOXO3 were found to be downregulated in IMPCs; their protein products play a role in cell polarity control. SEC63 protein also plays a role in trafficking of proteins in ciliogenesis. FOXO3 regulates LKB1 transcription. LKB1 protein has a role in maintaining cell polarity during cell division. These findings suggest the possible role of SEC63 and FOXO3 in altered polarity of IMPC cells (Gruel et al. 2014).
The most frequent amplifications were found on chromosome 17q22-q23.3. The second most common region recurrently amplified was the ERBB2 region (Gruel 2014). MYC amplification, compared to IBC NST cases, is significantly more common in pure IMPC. An interesting observation was, that despite these tumors belonging to the luminal molecular subtype, ESR1 amplification is not a common genomic alteration (Marchiò et al. 2008).
Consistent with the frequent ER expression observed in IMPCs, microarray-based gene expression profiling also revealed that these tumors frequently harbor genetic aberrations similar to those detected in IBCs of the luminal B subtype (Natrajan et al. 2014) (Molecular Subtypes of Breast Cancer).
When analyzing the transcriptomes of IMPC cases by deep sequencing, 45 microRNAs (miRNA) were shown differently expressed in IMPC and in IBC NST. A miRNA-specific RT qPCR-based analysis revealed significant differences of let-7b, miR-30c, miR-148a, miR-181a, and miR-181b expression levels between IMPCs and IBC NSTs (Li et al. 2012).
Promoter hypermethylation of leucine zipper putative tumor suppressor 1 (LZTS1), located on 8p – leading to downregulation of the gene – is frequently observed in IMPCs associated with LNM (Wang et al. 2015).
Serous ovarian carcinoma metastatic to the breast may mimic the histological features of IMPC and usually also displays lymphatic tumor emboli. However, the presence of psammoma bodies and the immunoreactivity for WT1 together with the clinical history may assist to make the right diagnosis. The caveat here is that IMPCs may express WT1, albeit infrequently (Lee et al. 2007).
IMPC should be distinguished from IBC NST with widespread lymphovascular invasion. Although the clear spaces around the morule-like clusters of IMPC cells resemble lymphatic channels, they are devoid of endothelial cell lining. The characteristic reverse polarity of IMPC cells is usually not observed in IBC NST.
Rare type of invasive breast cancer displaying tumor cell clusters in empty spaces. The tumor cells have inverse polarity.
The inverse polarity of tumor cells can be demonstrated by EMA immunohistochemistry.
The cells may form morule-like clusters or pseudotubules.
Lymphovascular invasion is a common feature.
IMPCs are usually ER/PR positive. Some cases belong to the HER2-positive subtype. Few IMPCs belong to the triple-negative non-basal group of breast carcinomas.
IMPCs are characterized by genetic heterogeneity. Gains and losses of large chromosomal segments are common. Genes responsible for cell polarity were found to be downregulated.
Wide excision with sentinel lymph node biopsy. IMPCs are more likely to develop axillary LN metastases than IBC NSTs.
According to recent large studies with follow-up data, the outcome is not worse than that of stage-matched ER-positive IBC NSTs. ER-negative IMPCs have poor prognosis.
Widespread lymphovascular invasion in IBC NST
Mucinous carcinoma with micropapillary features
Metastatic serous papillary ovarian carcinoma
Retraction artifact in poorly fixed specimens
References and Further Reading
- Gruel, N., Benhamo, V., Bhalshankar, J., Popova, T., Freneaux, P., Arnould, L., Mariani, O., Stern, M. H., Raynal, V., Sastre-Garau, X., Rouzier, R., Delattre, O., & Vincent-Salomon, A. (2014). Polarity gene alterations in pure invasive micropapillary carcinomas of the breast. Breast Cancer Research, 16, R46. https://doi.org/10.1186/bcr3653
- Marchiò, C., Iravani, M., Natrajan, R., Lambros, M. B., Savage, K., Tamber, N., Fenwick, K., Mackay, A., Senetta, R., Di Palma, S., Schmitt, F. C., Bussolati, G., Ellis, I. O., Ashworth, A., Sapino, A., & Reis-Filho, J. S. (2008). Genomic and immunophenotypical characterization of pure micropapillary carcinomas of the breast. The Journal of Pathology, 215, 398–410.CrossRefGoogle Scholar
- Marchiò, C., Iravani, M., Natrajan, R., Lambros, M. B., Geyer, F. C., Savage, K., Parry, S., Tamber, N., Fenwick, K., Mackay, A., Schmitt, F. C., Bussolati, G., Ellis, I., Ashworth, A., Sapino, A., & Reis-Filho, J. S. (2009). Mixed micropapillary-ductal carcinomas of the breast: A genomic and immunohistochemical analysis of morphologically distinct components. The Journal of Pathology, 218(3), 301–315.CrossRefGoogle Scholar
- Natrajan, R., Wilkerson, P. M., Marchiò, C., Piscuoglio, S., Ng, C. K., Wai, P., Lambros, M. B., Samartzis, E. P., Dedes, K. J., Frankum, J., Bajrami, I., Kopec, A., Mackay, A., A’Hern, R., Fenwick, K., Kozarewa, I., Hakas, J., Mitsopoulos, C., Hardisson, D., Lord, C. J., Kumar-Sinha, C., Ashworth, A., Weigelt, B., Sapino, A., Chinnaiyan, A. M., Maher, C. A., & Reis-Filho, J. S. (2014). Characterization of the genomic features and expressed fusion genes in micropapillary carcinomas of the breast. The Journal of Pathology, 232(5), 553–565.CrossRefGoogle Scholar
- Peterse, J. L. (1993). Breast carcinomas with an unexpected inside-out growth pattern: rotation of polarization associated with angioinvasion. (Abstract). Pathology Research and Practice, 189, 780.Google Scholar
- Weigelt, B., Horlings, H. M., Kreike, B., Hayes, M. M., Hauptmann, M., Wessels, L. F. A., de Jong, D., Van de Vijver, M. J., Van’t Veer, L. J., & Peterse, J. L. (2008). Refinement of breast cancer classification by molecular characterization of histological special types. The Journal of Pathology, 216, 141–150.CrossRefGoogle Scholar
- Yu, J. I., Choi, D. H., Huh, S. J., Cho, E. Y., Kim, K., Chie, E. K., Ha, S. W., Park, I. A., Ahn, S. J., Lee, J. S., Shin, K. H., Kwon, Y., Kim, Y. B., Suh, C. O., Koo, J. S., Kim, J. H., Jeong, B. G., Kim, I. A., Lee, J. H., & Park, W. (2015). Differences in prognostic factors and failure patterns between invasive micropapillary carcinoma and carcinoma with micropapillary component versus invasive ductal carcinoma of the breast: Retrospective Multicenter Case-Control Study (KROG 13-06). Clinical Breast Cancer, 15, 353-361.e351-352.Google Scholar