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Cystic hypersecretory (in situ) carcinoma (CHC) is an unusual and rare variant of ductal carcinoma in situ (DCIS) characterized by its cystic appearance, characteristic luminal secretion (resembling thyroid colloid), and micropapillary growth pattern.1,3,8 It was first described by Rosen and Scott in 1984.6 The outstanding morphologic feature is marked secretory activity with the formation of dilated ducts and cysts containing homogeneous, eosinophilic material which resembles thyroid colloid. 2,3,5 CHC is thought to behave in an indolent manner but has the potential to evolve into invasive carcinoma, which is often poorly differentiated.1,2,4,7
CHC is part of a spectrum of cystic hypersecretory lesions (CHL), which also includes cystic hypersecretory change/cystic hypersecretory hyperplasia (CHH) and CHH with atypia (atypical CHH). Microscopically all CHL have dilated ducts and cysts, which contain homogenous eosinophilic acellular secretion that bears a striking resemblance to thyroid colloid. These secretions usually retract from the surrounding epithelium with a smooth or scalloped margin. Defects in the secretion sometimes consist of folds, linear cracks, or small punched-out holes.1,3,5
Many of the cysts in CHL are lined by inconspicuous flat cells or single layer of cuboidal to columnar cells. When this is the only epithelial pattern with uniform cytologically bland nuclei and scant cytoplasm, the lesion is CHH. Atypical features like epithelial crowding, hyperchromasia, rare mitotic figures, and nuclei enlargement (which may contain nucleoli) result in atypical CHH. In CHC, the epithelium of some of the cysts and ducts grow as micropapillary intraductal carcinoma. In any one case, a spectrum of epithelial patterns is encountered, ranging from short, knobby epithelial tufts to complex branching fronds that may extend across the duct lumen. However, the so call Roman arch, or bridging pattern, commonly seen in other forms of micropapillary carcinoma, is uncommon in this lesion. A biopsy that consists entirely of cystic elements, lacking the papillary component, should be termed cystic hypersecretory hyperplasia rather than carcinoma. The nuclear grade is most often intermediate to poorly differentiate. High grade lesions exhibit more pronounced mitotic activity. Almost all invasive CHC have poorly differentiated ductal subtype with solid growth pattern without secretory features. Nuclei of invasive carcinoma cells may have a clear vacuolated appearance, similar to the pattern observed in papillary thyroid carcinoma.1,2,3,6,8
CHL can be diagnosed in fine needle aspirations (FNA) specimen if the secretion is recognized. The colloid-like secretory material together with a residual lump after aspiration should raise a strong suspicion of CHC. Epithelial cells in clusters and individually may be found amidst the secretory material. Lesions with intraductal carcinoma usually produce papillary clusters of tumor cells in an FNA specimen.3,4
The differential diagnosis for CHL includes entities with gross and microscopic cyst formation and/or prominent secretion. Secretory carcinoma (SC), is a low-grade invasive carcinoma characterized by eosinophilic luminal secretion and cells with vacuolated cytoplasm. In contrast to larger dilated cysts seen in CHL, SC glands show microcystic pattern in which the glands have “honeycomb” appearance. SS is microscopically infiltrative and present in a sclerotic stroma. CHC differs from SC by its in-situ nature, presence of large dilated cysts, and a more homogeneous intraductal micropapillary pattern. SC is ER-, S100+ and shows a characteristic ETV6-NKRK3 gene fusion, which is detected by fluorescence in situ hybridization.3,6,8
CHH sometimes coexists with pregnancy-like hyperplasia (PLH), and aspects of the two conditions seem to overlap when this occurs. PLH is typically described as glands and terminal ducts with swollen glandular cells and abundant pale-to-clear vacuolated cytoplasm. Some nuclei are contained in blebs of cytoplasm that are extruded into the glandular lumen. The luminal cytoplasmic borders of glandular cells are frayed. PLH usually has little or no secretion.5
Fibrocystic changes are radiographically indistinguishable from CHL but can easily be distinguished by microscopy.3
Another entity to consider in the differential diagnosis is juvenile papillomatosis (JP), which is a localized cystic process that may present clinically as a mass.1 JP is differentiated from CHC by its characteristic presentation in adolescents as a “Swiss cheese” pattern associated with ductal papillomatosis, papillary hyperplasia, sclerosing adenosis, and varying degrees of epithelial atypia.6 Secretions, when observed, are similar to those seen in fibrocystic changes and lack the characteristic colloid-like secretions seen in CHL.3
Finally, CHC should be distinguished from conventional micropapillary DCIS. Luminal secretions are not atypical feature of micropapillary DCIS. Whereas CHC exhibits intermediate grade to high-grade nuclei, micropapillary DCIS ranges from low to high-grade nuclear proliferations. Micropapillary DCIS is often multifocal in distribution and detected on mammography because of its association with calcifications, whereas CHC tends to be a localized process that is frequently mass forming. Other patterns of DCIS (cribriform, solid, papillary) are often seen in combination with micropapillary DCIS; in most instances, CHC is entirely micropapillary and infrequently displays these other architectural patterns. Moreover, notably, conventional types of DCIS are not present in the surrounding breast tissue in cases of CHC.1
A deficiency in the current literature is the immunohistochemistry characterization CHC. Moreover, clinical follow-up information is available in less than half of the reported cases. Positive reactions for carcinoembryonic antigen (CEA), a-lactalbumin, periodic acid-Schiff (PAS), and faint mucicarmine staining have been observed in the cyst contents/secretions, which are consistently negative for thyroglobulin. Immunoreactivity for S-100 has also been observed. Myoepithelial cells that are reactive with various myoepithelial markers outlined epithelial cells in CHC. Estrogen and progesterone immunohistochemistry show varying reactivity and hence nonspecific.1,3,6
Because CHH is grossly and radiographically indistinguishable from CHC and as CHC is often present in a background of CHH, excisional biopsy is recommended when CHH is identified in a needle core biopsy. Clinically, patents diagnosed with CHC typically have an excellent prognosis and experience long-term disease-free survival. Therapeutic options for patients with CHC are similar to those available to women with other forms of ductal carcinoma. Mastectomy has proved to be curative for most women with intraductal lesions. When invasive carcinoma is present, sentinel lymph node mapping should be performed. Intraductal CHC has the same low-grade clinical course as other forms of intraductal carcinoma. Because invasive carcinoma arising in this setting appears to be histologically high-grade, it is important to recognize and promptly treat the lesion while still in its in situ phase. 1,3,7
Cystic hypersecretory (in situ) carcinoma of breast is a very rare disease. Familiarity with the morphology is key for pathologists to avoid misdiagnosis.
References:
1. D'Alfonso TM, Ginter PS, Liu YF, Shin SJ. Cystic hypersecretory (in situ) carcinoma of the breast: a clinicopathologic and immunohistochemical characterization of 10 cases with clinical follow-up. Am J Surg Pathol. 2014 Jan;38(1):45-53.
2. Rosen PP, Scott M. Cystic hypersecretory duct carcinoma of the breast. Am J Surg Pathol. 1984;8:31–41.
3. Syed Hoda-Paul Rosen - Rosen's breast pathology. Wolters Kluwer Health/Lippincott Williams & Wilkins – 2008
4. Schmitt, F. and E. Tani . Cytological findings in cystic hypersecretory ductal carcinoma of the breast: a potential pitfall in mammary cytology. Cytopathology 2000. 11:513–519.
5. Shin SJ, Rosen PP. Pregnancy-like (pseudolactational) hyperplasia: a primary diagnosis in mammographically detected lesions of the breast and its relationship to cystic hypersecretory hyperplasia. Am J Surg Pathol. 2000;24:1670–1674.
6. Resetkova E, Padula A, Albarraccin CT, et al. Pathologic quiz case: a large, ill-defined cystic breast mass. Invasive cystic hypersecretory duct carcinoma. Arch Pathol Lab Med. 2005;129:e79–e80.
7. Guerry P, Erlandson RA, Rosen PP. Cystic hypersecretory hyperplasia and cystic hypersecretory duct carcinoma of the breast. Pathology, therapy, and follow-up of 39 patients. Cancer. 1988;61:1611–1620.
8. Tan PH, Sahin AA – Atlas of differential diagnosis in breast pathology. Springer-Verlag New York – 2018