Encyclopedia of Pathology

Living Edition
| Editors: J.H.J.M. van Krieken

Invasive Secretory Carcinoma

  • Angelo SidoniEmail author
Living reference work entry
DOI: https://doi.org/10.1007/978-3-319-28845-1_4721-1


Juvenile secretory carcinoma, Juvenile breast carcinoma, Secretory carcinoma.


Invasive secretory carcinoma (ISC) is one of the rarest histological subtypes of breast cancer, of low-grade and translocation-associated. ISC shows distinctive histological features consisting in intracellular and extracellular production of secretory material.

Clinical Features

  • Incidence: Less than 0.15% of all breast carcinomas (about 200 cases published in English literature).

  • Age: Originally described in children and termed “juvenile secretory carcinoma” (McDivitt and Stewart 1966), it appears that two thirds of the published cases actually occur in adults and very rarely in the elderly. The age range of the reported cases varies from 3 to 91 years.

  • Sex: Mainly observed in adult female and children of both sexes, very rare in men over the age of 30. A case in a male-to-female transgender has been described (Grabellus et al. 2005).

  • Site: ISC may appear in any part of the breast; however, a subareolar location is prevalent, particularly in men and children, and frequently associated with nipple discharge. The usual clinical presentation is a slow growing nodule, mobile, often present for a long time and easily mistaken with a fibroadenoma or a papilloma on imaging studies. Rare cases are reported in the axilla, conceivably originating from ectopic breast tissue or from skin appendage glands.

  • Treatment: Treatment varies depending on the age and sex of patients. In children, considering the favorable prognosis and the need to safeguard the development of the breast, a conservative local excision is the most advisable treatment. In post-menarchal girls and women wide local excision, quadrantectomy, or mastectomy are reported based on tumor dimensions in order to obtain negative surgical margins. In males, due to small dimension of breast, mastectomy is the rule. Sentinel lymph node mapping is suggested. No definitive conclusions are available on the benefits of systemic adjuvant chemotherapy and radiotherapy.

  • Outcome: The clinical course of ISC is mainly characterized by favorable prognosis and a prolonged survival, particularly in children and young adults under 30 years of age, even in presence of lymph node metastasis (rarely are involved more than three lymph nodes). In adult women ISC are more aggressive, especially if the tumor is of high-grade (see below) and locally advanced, although distant metastases are exceptional and still correlated with long survival. Late local recurrence (even after 20 years) may occur and a prolonged follow-up is necessary.


ISC usually presents as a single firm nodule, with well-defined smooth contour and a mean diameter of 3 cm (range 0.5–12.5). The cut surface may be lobulated with a central area of fibrosis and a color variable from grayish-white to yellow-tan. Occasionally margins may be spiculated and the tumor may show microcystic nature with spongy consistency. Multifocality is very uncommon.


In prototypical ISCs tumor cells are arranged in varying patterns with a tubular, follicular, microcystic (honeycomb) solid, and papillary architecture (Fig. 1 H&E). Fibrous septa crossing the mass may be present, explaining its lobulated appearance. A striking feature is the presence of abundant extracellular eosinophilic secretory material reminiscent of thyroid colloid (Fig. 2 H&E). Tumor borders are usually pushing but infiltrative growth in the surrounding tissues may be observed (Fig. 3 H&E).
Fig. 1

Coexistence of solid, microcystic, follicular, tubular, and papillary patterns

Fig. 2

Honeycomb pattern resembling thyroid follicles

Fig. 3

Despite the well circumscribed appearance, invasion is present at the border

Tumor cells show a variable combination of secretory and apocrine features (Koerner 2014). Secretory cells have a pale cytoplasm with numerous vacuoles containing eosinophilic material. Nuclei display low-grade features and are small and ovoid with inconspicuous nucleoli. Cells with apocrine features are polygonal with abundant granular and eosinophilic cytoplasm, and their nuclei are round and uniform with discrete nucleoli. Mitotic activity and necrosis are usually absent. An in situ component is often present with growth patterns similar to those seen in conventional invasive carcinoma of no special type, mainly of low grade (cribriform and papillary), but with the same cytological features of the invasive ISC. Microcalcifications are rare or absent.

Both intracellular and extracellular secretory material is diastase-PAS positive (Fig. 4 PAS staining) and sialidase-Alcian blue (Fig. 5 Alcian blue) positive, indicating a composition rich in acidic mucins, particularly sulfated mucopolysaccharides and sialomucins.
Fig. 4

Diastase-periodic-acid-Schiff positivity of extracellular secretory material

Fig. 5

Sialidase-Alcian blue positivity of extracellular secretory material

The above histological description is consistent with almost all cases of ISC; however, a small subset of patients may present morphological aspect of aggressiveness (prevalent solid pattern, scant secretory activity, strong nuclear atypia, high mitotic rate, necrosis, peritumoral lymphovascular involvement, and metastatic behavior), which seems to correlate with a specific genomic profile (Del Castillo et al. 2015).

At ultrastructural level tumor cells contain secretory intracytoplasmic membrane-bound vacuoles, bound with desmosome and grouped in clusters partially surrounded by a basal lamina. Large extracellular spaces are occupied by secretory material.

Concluding the microscopic description of ISCs, it is worth noting the singular resemblance of ISC with a newly described salivary gland tumor named “mammary analogue secretory carcinoma” (MASC). As the name implies, this entity shows morphological, immunohistochemical, and genetic characteristics similar to those of the breast counterpart. A cutaneous variant of secretory carcinoma has been recently proposed (Bishop et al. 2017).


Immunohistochemically most of the ISC are triple-negative (absence of estrogen receptors, progesterone receptors, and HER2) and positive for cytokeratin (CK) 5/6 and/or CK14 and for epidermal growth factor receptor (EGFR), which confirm a basal-like phenotype. S-100 protein is typically strongly expressed as well as the signal transducer and activator of transcription 5A (STAT5a). Other markers, consistently expressed, include epithelial membrane antigen (EMA), and lactalbumin, while variable reactivity was observed for polyclonal CEA, gross cystic disease fluid protein-15 (GCDFP-15), E-cadherin, and CD117. Tumor cells may at least focally express CKs 8/18, 19, and various CK cocktails. Myoepithelial cells are absent thus alpha-smooth-muscle actin, calponin, and p63 are negative. Reported Ki67 indexes varied from less than 1–50%.

Molecular Features

The most relevant and specific molecular alteration in ISC consists in a recurrent balanced chromosomal translocation, t(12;15) (p13;q25) with an ETS variant 6–neurotrophic receptor tyrosine kinase 3 (ETV6–NTRK3) fusion gene (Tognon et al. 2002). This translocation had already been described in pediatric spindle cell tumors, such as infantile fibrosarcoma and cellular congenital mesoblastic nephroma, in some myeloid acute leukemia, and, subsequently, in mammary analogue secretory carcinoma (MASC) of the salivary gland.

Differential Diagnosis

If the pathologist has sufficient material, the diagnosis of ISC, despite its rarity, does not present any particular problems. Some difficulties may arise in cases with predominant apocrine aspects or against the recently described mammary acinic carcinoma. However, looking for a typical histological pattern of ISC, the presence of intracellular and extracellular secretory material, tumor cells with granular eosinophilic to foamy cytoplasm and immunohistochemical features (triple-negative and S-100-positive) are helpful for the diagnosis. In difficult cases, FISH detection of an ETV6 rearrangement can be used to make a correct diagnosis. On the contrary differential diagnosis with other lesions containing secretory aspects based on core needle biopsies or fine needle aspiration cytology may be particularly challenging given their pathologic spectrum and frequently subtle morphology (Toll et al. 2016).

References and Further Reading

  1. Bishop, J. A., Taube, J. M., Su, A., Binder, S. W., Kazakov, D. V., Michal, M., & Westra, W. H. (2017). Secretory carcinoma of the skin harboring ETV6 gene fusion. A cutaneous analogue to secretory carcinomas of the breast and salivary glands. American Journal of Surgical Pathology, 41, 62–66.CrossRefPubMedGoogle Scholar
  2. Del Castillo, M., Chibon, F., Arnould, L., Croce, S., Ribeiro, A., Perot, G., Hostein, I., Geha, S., Bozon, C., Garnier, A., Lae, M., Vincent-Salomon, A., & MacGrogan, G. (2015). Secretory breast carcinoma. A Histopathologic and genomic Spectrum characterized by a joint specific ETV6-NTRK3 gene fusion. American Journal of Surgical Pathology, 39, 1458–1467.CrossRefPubMedGoogle Scholar
  3. Grabellus, F., Worm, K., Willruth, A., Schmitz, K. J., Otterbach, F., Baba, H. A., Kimming, R., & Metz, K. A. (2005). ETV6-NTRK3 gene fusion in a secretory carcinoma of the breast of a male-to-female transsexual. The Breast, 14, 71–74.CrossRefPubMedGoogle Scholar
  4. Koerner, F. C. (2014). Secretory carcinoma. In S. A. Hoda, E. Brogi, F. C. Koerner, & P. P. Rosen (Eds.), ROSEN's BREAST pathology (4th ed., pp. 689–701). Philadelphia: Wolters Kluwer Lippincott Williams & Wilkins.Google Scholar
  5. McDivitt, R. W., & Stewart, F. W. (1966). Breast carcinoma in children. JAMA, 195, 388–390.CrossRefPubMedGoogle Scholar
  6. Tognon, C., Knezevich, S. R., Huntsman, D., Roskelley, C. D., Melnyk, N., Mathers, J. A., Becker, L., Carneiro, F., MacPherson, N., Horsman, D., Poremba, C., & Sorensen, P. H. (2002). Expression of the ETV6-NTRK3 gene fusion as a primary event in human secretory breast carcinoma. Cancer Cell, 2, 367–376.CrossRefPubMedGoogle Scholar
  7. Toll, A., Joneja, U., & Palazzo, J. (2016). Pathologic spectrum of secretory and mucinous breast lesions. Archives of Pathology and Laboratory Medicine, 140, 644–650.CrossRefPubMedGoogle Scholar

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© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Medical School, Section of Pathologic Anatomy and Histology, Department of Experimental MedicineUniversity of PerugiaPerugiaItaly