Invasive Oncocytic Carcinoma
Invasive oncocytic carcinoma (OC) is a “special type” of breast carcinoma that is composed of at least 70% of cells with oncocytic features (so-called oncocytes) on both morphologic and immunophenotypic grounds (Lakhani et al. 2012).
Oncocyte is a Greek term, first applied to salivary glands by Hamperl (1931) in 1931, which means “swollen cell.” Under light microscope, oncocytes are characterized by abundant granular eosinophilic cytoplasm due to a high content of mitochondria, demonstrable at ultrastructural level (Roth et al. 1962). By definition, mitochondria must occupy at least 60% of the total cytoplasmic volume (Ghadially 1985) and confer an intense cytoplasmic granular positivity for anti-mitochondrion antibody (Damiani et al. 1998; Ragazzi et al. 2011). Namely, a carcinoma can be classified as oncocytic if it shows a strong cytoplasmic positivity for anti-mitochondrion antibody in at least 70% of tumor cells.
This tumor is considered very rare, but is suspected to be overlooked, and probably misdiagnosed as apocrine carcinoma. The largest series on record retrospectively evaluating 76 consecutive breast carcinomas using immunohistochemistry for anti-mitochondrion reported an incidence of 19.6% (Ragazzi et al. 2011).
Thirty-seven cases of invasive oncocytic carcinoma have been reported in English-language literature. Among them, four cases occurred in men.
All breast quadrants can be affected and a multifocal and bilateral case has also been reported (Itagaki et al. 2017).
Clinical features of oncocytic carcinomas are similar to those of invasive carcinomas, no special type (NST) (“Invasive Carcinoma NST”) (Ragazzi et al. 2011). Thus, the therapeutic strategies are the same. Resistance to radiotherapy has been hypothesized just as it has been reported in oncocytic tumors at other sites, including the rectum, thyroid, and meninges, but it has been never investigated in the breast.
Presently, knowledge available on the prognostic impact of oncocytic differentiation in breast carcinomas is scant. According to the largest series reported (Ragazzi et al. 2011), prognosis depends on grading and staging and is similar to the matched breast carcinomas NST (“Invasive Breast Carcinoma NST”).
Tumor size ranges from 0.8 to 9 cm (mean 3 cm). On cut section, OCs are mainly well-defined, solid, and firm, from whitish to tan brown nodules.
By definition, OCs show an intense and diffuse anti-mitochondrion positivity in at least 70% of tumor cells (Ragazzi et al. 2011).
In addition, OCs have mostly a “luminal” phenotype with expression of CK7, EMA, and consistent positivity for hormone receptors. HER2 positivity has been detected in 25% of tested cases. Few triple-negative cases are also on record, and in these cases, androgen receptor (AR) should be performed to rule-out apocrine differentiation. Most importantly, a tall cell variant of papillary breast carcinoma should be excluded: it is AR negative and can co-express luminal-markers (CK7, EMA, GATA 3), S100, and basal-type cytokeratins (CK5 or CK5/6) (Bhargava et al. 2017).
Using the array comparative genomic hybridization (aCGH) technique on a cohort of OCs and mitochondrion-rich breast carcinomas compared with matched invasive ductal carcinomas NST, Geyer et al. found that the formers are characterized by gains of 5p13.33, 11q13.1-q13.2, 16p13.3, 17q25.3, and 19p13 (Geyer et al. 2012). These chromosomal regions host several nuclear genes with mitochondrial functions (Geyer et al. 2012). Intriguingly, in the 5p13.33 region, the Telomerase Reverse Transcriptase (TERT) gene has been mapped and it has been established that TERT protein can localize to the mitochondrion and modulate its activity (Sahin et al. 2011). Based on these data, Geyer et al. concluded that OCs of the breast are a group of tumors with a distinctive pattern of chromosomal aberrations, previously associated with OCs of other anatomical sites (e.g., oncocytic tumors of the kidney and thyroid) (Geyer et al. 2012).
A recent in vitro study, performed on six breast cancer cell lines, investigated the role of SIRT/FOXO/SOD2 axis of the mitochondrial unfolded protein response in promoting breast tumor invasiveness. In the same paper, Kenny et al. found a notably increase of SOD2 immunostaining in a series of OC breast carcinomas compared with non-OC. These high SOD2 levels seem to be correlated with the high activity of the SIRT/FOXO/SOD2 axis. Moreover, the authors observed that patients with high SOD2 expression tumors had a significantly worse outcome and that a SOD2 positive expression correlated with lymph nodal involvement (Kenny et al. 2017).
Carcinoma with apocrine differentiation (“Apocrine Carcinoma”): The differential diagnosis between OC and carcinomas with apocrine features is usually difficult on morphology and mainly relies on immunohistochemistry. Apocrine carcinomas are positive for GCDFP-15 and AR, while hormone receptors are typically negative and antibodies for mitochondria are seen in cells below 50% of the total neoplastic proliferation. Occasional cases, however, are oncocytic and apocrine at the same time.
Acinic cell carcinoma (ACC) (“Acinic Cell Carcinoma”): Granular cytoplasm in ACC is due to zymogen granules that are evidenced by PAS after diastase digestion. Anti-mitochondrion antibodies are negative. Tumor cells in ACC show serous differentiation and are positive with salivary type amylase, lysozyme, and alpha-1-antichimotrypsin immunostains. In addition, ACC cells are typically immunoreactive for S-100 and they are triple negative with no expression of both estrogen and progesterone receptors and no Her2 amplification.
Neuroendocrine carcinoma (“Invasive Carcinoma with Neuroendocrine Differentiation”): Well-differentiated neuroendocrine carcinoma of the breast could be very similar to low-grade OC. Expression of chromogranin and/or synaptophysin in the majority of tumor cells is characteristic of neuroendocrine differentiation.
Granular cell tumors (“Granular Cell Tumor”): They are composed of cells with eosinophilic granular cytoplasm that can mimic oncocytes, but they derive from Schwann cells of peripheral nerves. Accordingly, neoplastic cells in granular cell tumors are strongly and diffusely positive for S100 and CD68 immunostains while they are negative for keratins.
References and Further Reading
- Bhargava, R., Florea, A. V., Pelmus, M., Jones, M. W., Bonaventura, M., Wald, A., & Nikiforova, M. (2017). Breast tumor resembling tall cell variant of papillary thyroid carcinoma: A solid papillary neoplasm with characteristic immunohistochemical profile and few recurrent mutations. American Journal of Clinical Pathology, 147, 399–410.CrossRefPubMedPubMedCentralGoogle Scholar
- Foschini, M. P., Asioli, S., Foreid, S., Cserni, G., Ellis, I. O., Eusebi, V., & Rosai, J. (2017). Solid papillary breast carcinomas resembling the tall cell variant of papillary thyroid neoplasms: A unique invasive tumor with indolent behavior. American Journal of Surgical Pathology, 41, 887–895.CrossRefGoogle Scholar
- Geyer, F. C., de Biase, D., Lambros, M. B., Ragazzi, M., Lopez-Garcia, M. A., Natrajan, R., Mackay, A., Kurelac, I., Gasparre, G., Ashworth, A., Eusebi, V., Reis-Filho, J. S., & Tallini, G. (2012). Genomic profiling of mitochondrion-rich breast carcinoma: Chromosomal changes may be relevant for mitochondria accumulation and tumour biology. Breast Cancer Research and Treatment, 132, 15–28.CrossRefGoogle Scholar
- Ghadially, F. N. (1985). Diagnostic electron microscopy of tumours (2nd ed.). London: Butterworth & Company.Google Scholar
- Hamperl, H. (1931). Beiträge zur normalen und pathologischen Histologie menschlieher Speicheldriisen. Zeitschrift für Mikroskopisch-Anatomische Forschung, 27, 1–55.Google Scholar
- Itagaki, H., Yamamoto, T., Hiroi, A., Kawanishi, K., Noguchi, E., Ohchi, T., Kamio, T., Kameoka, S., Oda, H., & Nagashima, Y. (2017). Synchronous and bilateral oncocytic carcinoma of the breast: A case report and review of the literature. Oncology Letters, 13, 1714–1718.CrossRefPubMedPubMedCentralGoogle Scholar
- Kenny, T. C., Hart, P., Ragazzi, M., Sersinghe, M., Chipuk, J., Sagar, M. A. K., Eliceiri, K. W., LaFramboise, T., Grandhi, S., Santos, J., Riar, A. K., Papa, L., D'Aurello, M., Manfredi, G., Bonini, M. G., & Germain, D. (2017). Selected mitochondrial DNA landscapes activate the SIRT3 axis of the UPRmt to promote metastasis. Oncogene, 36, 4393–4404.CrossRefPubMedPubMedCentralGoogle Scholar
- Lakhani, S. R., Ellis, I. O., Schnitt, S. J., Tan, P. H., & van de Vijver, M. J. (2012). WHO classification of tumours of the breast (4th ed.). Lyon: IARC.Google Scholar
- Sahin, E., Colla, S., Liesa, M., Moslehi, J., Muller, F. L., Guo, M., Cooper, M., Kotton, D., Fabian, A. J., Walkey, C., Maser, R. S., Tonon, G., Foerster, F., Xiong, R., Wang, Y. A., Shukla, S. A., Jaskelioff, M., Martin, E. S., Heffernan, T. P., Protopopov, A., Ivanova, E., Mahoney, J. E., Kost-Alimova, M., Perry, S. R., Bronson, R., Liao, R., Mulligan, R., Shirihai, O. S., Chin, L., & DePinho, R. A. (2011). Telomere dysfunction induces metabolic and mitochondrial compromise. Nature, 470, 359–365.CrossRefPubMedPubMedCentralGoogle Scholar