A 61 year-old woman presented to her physician after roticing a firm mass in her right breast. Physical examination revealed a firm, palpable mass in the superior outer quadrant of the right breast. Mammography demonstrated an irregular, spiculated mass with areas of calcification. Needle localization excision of the mass was performed, revealing a 2.5-cm, tan-yellow, stellate, gritty mass. Light microscopic examination of hematoxylin-eosin-stained sections revealed a moderately differentiated neoplasm composed of infiltrating nests of atypical cells (Figure 1) with abundant clear cytoplasm (Figure 2). The tumor demonstrated abundant intracytoplasmic staining with periodic acid-Schiff (PAS) stain (Figure 3). The PAS staining after diastase treatment was negative (Figure 4). The cells were immunoreactive for E-cadherin, cytokeratin 7, and gross cystic disease fluid protein 15 (GCDFP-15). The cells were negative for cytokeratin 20 and mucin.
What is your diagnosis?
Pathologic Diagnosis: Glycogen-Rich Clear Cell Carcinoma of the Breast
Glycogen-rich clear cell carcinoma (GRCCC) of the breast is defined as a carcinoma in which more than 90% of the neoplastic cells have abundant clear cytoplasm containing glycogen.1 It is a rare tumor, with an incidence of 0.9% to 3% of all breast malignancies.2-4 The neoplastic cells often form invasive nests, cords, or papillary structures and may or may not be associated with an intraductal component. The cells have abundant clear cytoplasm that contains PAS-positive diastase-labile material, consistent with glycogen. Apocrine features are often observed in GRCCCs. Hayes et al1 demonstrated apocrine features in 13 (62%) of 21 GRCCCs. This finding suggests that GRCCC may be a variant of apocrine carcinoma in which the cytoplasm has lost its eosinophilic appearance and has become clear. Some authors3 claim that GRCCC of the breast portends a poorer prognosis compared with conventional ductal carcinomas. However, others1,5 contend that the prognosis of GRCCC is no different than that of conventional ductal carcinoma once tumors are matched by size, grade, and lymph node status.
Many other primary neoplasms of the breast may demonstrate cytoplasmic clearing and should be considered in the differential diagnosis of clear cell breast lesions, including secretory, lipid-rich, apocrine, and mucinous carcinomas. Secretory carcinoma, although originally described in children, may also be seen in adults.6 The tumor consists of glands and microcystic spaces that contain abundant pink, often foamy, secretions. The cells have pale-to-pink, amphophilic cytoplasm and nuclei of low grade. The cytoplasm often appears clear or vacuolated, corresponding to intracytoplasmic lumina seen ultrastructurally. The cells are negative for glycogen, as demonstrated by the PAS stain. Lipid-rich carcinoma, accounting for less than 1% of primary breast malignancies, is composed of clear cells that contain large quantities of lipid, demonstrated by oil red O or Sudan IV methods.7 However, these methods can only be applied successfully to fresh, unfixed tissue. The nuclei of lipid-rich carcinoma are generally small and dark and the cytoplasm clear to vacuolated. Importantly, the cells are generally positive for GCDFP-15 and negative for glycogen or mucin. Apocrine carcinoma, also accounting for less than 1% of breast carcinomas, has cytologic features consistent with apocrine differentiation. The nuclei often have hyperchromatic and irregular membranes with prominent, eosinophilic nucleoli. In most cases, the cytoplasm exhibits dense eosinophilia that may be homogenous or granular. Apical apocrine "snouts" may also be appreciated. Although less common, cytoplasmic clearing has also been described, imparting a clear cell morphologic structure. Mucinous or "colloid" carcinoma is characterized by the presence of malignant cells floating in large quantities of extracellular mucin. Intracellular mucin may not be prominent. The malignant epithelial cells are arranged in a variety of patterns (sheets, nests, papillae, tubules), and cytoplasmic clearing or foaminess, although not a salient feature, has rarely been described. Clear cell change has also been described in the cytoplasm of neuroendocrine tumors of the breast. These tumors, however, often have characteristic nuclear features of neuroendocrine neoplasms and will generally be positive for one or more neuroendocrine markers. Pleomorphic lobular or "histiocytoid carcinoma" of the breast may be composed of clear cells. However, these cells lack glycogen and are negative for E-cadherin.
Myoepithelial lesions, such as myoepithelial hyperplasia, myoepithelioma, and adenomyoepithelioma, also enter into the differential diagnosis of clear cell lesions of the breast. Mammary lesions composed entirely or in part of myoepithelial cells, myoepitheliomas, and adenomyo-epitheliomas are relatively uncommon/ Nonetheless, both in situ and infiltrating forms of clear cell myoepithelioma have been described.8 The cells of myoepitheliomas are generally spindled shaped. Adenomyoepitheliomas are composed of 2 cell types, an inner epithelial cell layer and an outer spindled or polygonal cell layer. Clear cell change is often prominent in both due to accumulation of glycogen. Myoepithelial cells are positive for SlOO protein and smooth muscle actin and have the characteristic ultrastructural features of myoepithelial cells.9
Numerous other "clear cell" entities may involve the breast in a primary or secondary fashion. This includes many primary cutaneous conditions that may impart a clear cell morphologic structure, including eccrine acrospiroma (clear cell hidradenoma), sebaceous neoplasms, clear cell papulosis, and malignant melanoma. Metastatic clear cell lesions, in particular, renal cell carcinoma, must be entertained in the differential diagnosis. Circumscription, lack of an in situ component, delicate vascular pattern, and negativity for cytokeratin 7 favor this diagnosis.
Clear cells are common in both healthy and pathologic breast tissue. This feature may be indicative of the presence of a cytoplasmic mucosubstance (lipid, mucin, glycogen) or suggestive of apocrine, endocrine, or myoepithelial differentiation. Therefore, the differential diagnosis of clear cell neoplasms of the breast is vast, including numerous primary benign and malignant neoplasms and those affecting the breast in a secondary fashion. Glycogen-rich clear cell carcinoma is distinguished by the presence of abundant PAS labile glycogen within the cytoplasm of the malignant cells.
1. Hayes Malcolm MM, Seidman JD, Ashton MA. Glycogen-rich clear cell carcinoma of the breast: a dinicopathologic study of 21 cases. Am J Surg Pathol. 1995:19:904-911.
2. Hull MT, Priest JB, Broadie TA, et al. Glycogen-rich clear cell carcinoma of the breast: a light and electron microscopic study. Cancer. 1981;48:2003-2009.
3. Fisher ER, Tavares J, Bulatao IS, et al. Glycogen-rich clear cell breast cancer: with comments concerning other clear cell variants. Hum Pathol. 1985;16:1085-1090.
4. Hull MT, Warfel KA. Glycogen-rich clear cell carcinomas of the breast: a dinicopathologic and ultrastructural study. Am J Surg Pathol. 1986;10:553-559.
5. Dina R, Eusebi V. Clear cell tumors of the breast. Semin Diagn Pathol. 1997; 14:175-182.
6. Akhtar M, Robinson C, Ali MA, Godwin JT. Secretory carcinoma of the breast in adults: light and electron microscopic study of three cases with review of the literature. Cancer. 1993:51:2245-2255.
7. Rosen PP. Glycogen-rich carcinoma. In: Rosen's Breast Pathology. 2nd ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2001:557-559.
8. Soares J, Tomasic G, Bucciarelli E, Eusebi V. Intralobular growth of myoepithelial cell carcinoma of the breast. Virchows Arch. 1994;425:205-210.
9. Kiaer H, Nielsen B, Paulsen S, et al. Adenomyoepithelial adenosis and low grade malignant adenomyoepithelioma of the breast. Virchows Arch A Pathol Anat Histopathol. 1984:405:55-67.
Jacqueline K. Trupiano, MD; Eric Ogrodowczyk, MD; Simon Bergman, MD
Accepted for publication July 10, 2003.
From the Department of Pathology, Wake Forest University Baptist Medical Center, Winston-Salem, NC.
Corresponding author: Simon Bergman, MD, Department of Pathology, Wake Forest University Baptist Medical Center, Medical Center Blvd, Winston-Salem, NC 27157-1072 (e-mail: sbergman@wfubmc. edu).
Reprints not available from the author.
Copyright College of American Pathologists Dec 2003
Provided by ProQuest Information and Learning Company. All rights Reserved