Clear cell hidradenoma of the breast with MAML2 gene rearrangement.

Yanping Hu and Li Luo diagnosed this case. Li Luo was responsible for collecting information and reviewed the literature, and contributed to manuscript drafting. Yanping Hu was responsible for revising the manuscript and guiding the writing of the manuscript. All authors contributed to the article and approved the submitted version.

The study involving human participants was reviewed and approved by the Ethics Committee of the Beijing Luhe Hospital, Capital Medical University (2023‐LHKY‐095‐02) and was conducted in accordance with the Declaration of Helsinki of 1975. Patients/participants provided written informed consent for their participation in this study. Written informed consent was obtained from individuals for the publication of any potentially identifiable images or data contained herein.

A 53‐year‐old female patient inadvertently discovered a painless peanut‐sized mass in her left breast six months ago, which gradually increased in the past two months. The patient had no family history of tumor or other similar medical history. A specialist physical examination found a mass in the left upper outer breast quadrant below the areola. The mass was approximately 1.0 × 1.0 cm, and was slightly hard, with an unsmooth surface, irregular shape, unclear boundary, and no obvious adhesion to the surface of the skin. There was no discharge from the nipple. No obvious mass was found in the right breast, and there were no significantly enlarged lymph nodes in the bilateral axilla. Breast color ultrasonography showed a solid cystic nodule located in the areola area in the left upper quadrant 1 cm from the nipple, with a size of about 1.0 × 0.8 cm, clear boundaries, and enhanced peripheral echo (Figure  1a ). Finally, mammography showed an irregular high‐density nodule in the inner 1/3 of the left outer breast quadrant with a few surrounding calcification points (Breast Imaging Reporting and Data System: Class 4b) (Figure  1b ). Color ultrasonography of the patient's left breast showed a solid cystic nodule in the outer upper quadrant 1 cm from the areola, with a size of about 1.0 × 0.8 cm, clear boundaries, enhanced peripheral echo, and stripe blood flow signals in the parenchyma (a). Mammography showed an irregular dense nodule (yellow arrow) in the inner 1/3 of the left outer breast quadrant with a few calcification points (BI‐RADS: Class 4b) (b).

In 1968, Finck et al. 2 first reported CCH of the breast, a tumor that occurs in the areola region and deep breast tissue. 2 , 4 , 5 , 6 This type of tumor can occur in both males and females 2 , 4 and cases have since been reported in patients whose ages ranged from 18 to 75 years old. 3 , 8 CCH of the breast has a long course of disease, 12 and typically manifests as painless breast masses, and a small number of patients experience nipple discharge. 4 The morphological characteristics of CCH of the breast are similar to those of CCH of the skin eccrine gland. It presents as single and solitary nodule, mostly cystic and solid with clear boundaries. Critically, fine needle aspiration biopsy specimens can easily be misdiagnosed as malignant breast tumors. 9 Microscopically speaking, the tumor cells are composed of four different types of cells, but most of the tumor cells have a transparent cytoplasm, hence the name “clear cell hidradenoma.” 1 In addition to clear cells, epidermoid cells, and basaloid cells are also frequently present with this disease, but mucous cells are usually uncommon or occur only in focal collections. 1 , 22 Furthermore, the tumor cells are arranged in solid sheets and can also form tubular and adenoid structures covered with cuboidal luminal cells, which highlight the features of CCH. 1 , 22 Tumor cells with vesicular nuclear chromatin, irregular nuclear membrane, and occasionally nuclear furrows and distinct nucleoli suggest atypical hidradenoma. 13 CCH of the breast can also undergo malignant transformation 18 and malignant CCH can occur. 14 Immunochemically, the tumor cells highly express CK5/6, CK14, CK7, Cam5.2, p63, P40, epithelial membrane antigen (EMA), and weakly express GCDFP‐15, 4 but they do not express SMA, calponin, SMMHC, ER, PR, 11 , 20 HER2, or AR. The cuboidal cells express SOX10 and S‐100 to varying degrees but do not express p63. 20 , 21 , 22 , 23 Furthermore, the tumor cells contain PAS‐positive diastase‐digestive granules. 5 About 50%–75% of skin hidradenomas have translocations on Chromosomes 11 and 19 that result in a CREB‐regulated transcription coactivator 1( CRTC1 , formerly MECT1 ) rearranged with the MAML2 or the (rarer) CRTC3/MAML2 gene rearrangement. 1 At present, we found seven cases of breast CCH in four reports that have detected a MAML2 gene rearrangement. 6 , 15 , 20 , 22 Our patient is thus only the eighth reported case of CCH of the breast with the MAML2 gene rearrangement. In addition, Black et al. 22 identified a somatic mitogen‐activated protein kinase kinase kinase 1 (MAP3K1) nonsense mutation in one case of breast CCH and a germline BRCA2 mutation in one patient with breast cancer and CCH. This rare mutation may further distinguish the molecular features of breast CCH. The incidence of the MAML2 gene rearrangement in the breast CCH may be high, although the number of cases of this hidradenoma is small overall. CCH needs to be distinguished from intraductal papilloma with usual ductal hyperplasia (UDH) and adenomyoepithelioma. The tumor cells of CCH express p63 diffusely and do not express SMMHC and calponin, while in the intraductal papilloma with UDH and adenomyoepithelioma, p63, SMMHC, and calponin are positively located in the myoepithelium of the papillary axis and the periductal myoepithelium. 15 , 20 At present it is very challenging to distinguish between CCH of the breast and low‐grade MEC of the breast. 20 , 21 , 22 , 23 Both are rare breast tumors with similar morphology, immunophenotype, and molecular changes ( MAML2 gene rearrangement) 22 but with different biological behaviors. CCH is a benign tumor, but low‐grade MEC carries the potential risk of recurrence and metastasis. The most characteristic morphology of CCH is the formation of glandular structure, and the cuboidal cells covering the glandular lumen have been found to be positive for SOX10, MUC4, and S‐100 but negative for p63, 15 , 20 , 21 , 22 , 23 though MEC lacks this glandular structure and immunophenotype. 22 , 23 Moreover, although one case of pulmonary MEC has demonstrated a glandular structure, its histological and immunophenotypical features simulated those of type II pneumocytes. 20 Additionally, CCH is solitary cystic and solid nodule with clear tumor boundaries, 15 , 20 , 21 , 22 , 23 but MEC consists of multiple nodules with ill‐defined borders and microinvasion or extensive invasion, or accompanied by in‐situ MEC. 22 , 23 The origin of CCH of the breast is controversial. Domoto et al. 4 suggested that there may be two origins, the mammary duct and the skin eccrine gland. Cases with a tumor located in the deep breast tissue, without a direct relationship with the skin, extended to the intraduct, and accompanied by breast‐related lesions 6 may point to an origin in the mammary duct. We believe that our case originated from the mammary duct epithelia. The tumor was located in the mammary gland layer of the areola region. In addition, the thin pink secretion could be seen in both the mammary duct and the cystic tumor, indicating the cystic tumor was connected to the mammary duct. Finck et al. 2 believed that the multipotential reserve cells were the original basis for morphologically similar tumors in sweat glands and mammary glands. Boecker et al. 24 found that p63/CK5/CK14 immunophenotypic progenitor cells may be the histological basis for the development of squamous and epidermoid cell differentiated tumors in mammary gland and salivary gland tumors. We believe that a combination of the multipotential reserve cell theory and Boecker's study can reasonably explain how the breast can develop CCH similar to that of the skin eccrine glands, and p63/CK5/CK14 immunophenotypic progenitor cells may be the histological basis for this. In conclusion, we reported a rare case of a 53‐year‐old woman with a CCH originating in the mammary duct in the left areola region. Subtle histological and immunophenotypical differences may help to distinguish CCH of the breast from common breast tumors. In addition, the MAML2 gene rearrangement may be a molecular genetic characteristic of breast CCH.

Clear cell hidradenoma (CCH) is a rare benign eccrine gland neoplasm with ductal and glandular differentiation, also known as solid cystic hidradenoma and nodular hidradenoma. It appears most commonly in the trunk and limbs of patients located in the dermis of the skin and extends into the subcutaneous tissue. 1 However, the incidence of the breast CCH remains low and about 30 cases have been reported in the English literature to date (Table  1 ). Here, we report a case of breast CCH with mastermind like transcriptional coactivator 2 ( MAML2 ) gene rearrangement. Review of the CCH of the breast. Abbreviations: CCH, clear cell hidradenoma; F, female; M, male; NS, not specified.

The patient underwent resection of the left breast mass. The gross tissue was gray and gray‐yellow, with a size of 2.0 × 1.8 × 1.4 cm. A cystic solid mass of about 1.0 × 0.8 × 0.7 cm in size was visible with clear boundaries on the section. A low‐power microscope showed that the wall of the cystic mass was hyalinized fibrous tissue with lymphocyte aggregation, and thin pink secretion was visible in the cyst (Figure  2a ). The tumor cells in the cyst were arranged in a solid structure (Figure  2b ) that was locally arranged in a glandular structure, covered by a single cuboidal cell (Figure  2c ). Three types of tumor cells were present. First, there were basaloid cells, with polygonal and cuboidal shapes, poorly defined cell boundaries, moderate eosinophilic cytoplasm, and round and oval nuclei. Second, there were epidermoid cells, with polygonal appearances, abundant eosinophilic cytoplasm, and unclear cell boundaries. Third, there were clear cells, with polygonal shapes, abundant transparent cytoplasm, and clear cell boundaries. No mucous cells were identified. No pathological mitotic images or necrosis were observed (Figure  2d ). Mammary duct dilation could be seen around the tumor and thin pink secretion was visible in the mammary duct. Hematoxylin eosin staining of the breast clear cell hidradenoma. A solid cystic mass is enclosed by fibrous tissue in the breast tissue (a, ×20). The tumor cells were arranged in a solid manner (b, ×200). The tumor cells were arranged in a glandular structure covered with a single cuboidal cell (black stars) (c, ×200). The tumor cells were composed of clear cells (black arrows), epidermoid cells (yellow arrows), and basaloid cells (gray arrows) (d, ×400). Immunohistochemical staining revealed that the tumor cell expressed low‐molecular cytokeratins (Cam5.2) (Figure  3a ) and cytokeratin 7 (CK7), high‐molecular cytokeratin 5/6 (CK5/6) and cytokeratin 14 (CK14) (Figure 3b), p63 (Figure  3c ). The cuboidal cells in the glandular lumen were positive for sex‐determining region Y‐related HMG‐box 10 (SOX10) (Figure  3d ), and negative for p63 (Figure  3c , black stars). CD117 was used to stain the basaloid cells and the epidermoid cells (Figure  3e ). About 10% of the tumor cells have weakly to moderately expressed estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2) (1+). In addition, the tumor cells weakly expressed GATA binding protein 3 (GATA‐3), and the Ki67 positive index was about 5%. The tumor cells did not express progesterone receptor (PR), androgen receptor (AR), mammaglobin, gross cystic disease fluid protein‐15 (GCDFP‐15), smooth muscle myosin heavy chain (SMMHC), and calponin (Figure  3f ). Periodic acid‐Schiff (PAS) reaction revealed purple‐red granules in the cytoplasm of the tumor cells, that disappeared after digestion by diastase (D‐PAS). Alcian blue (AB) staining revealed no blue mucus in the cytoplasm. Dual‐color MAML2 break‐apart fluorescence in situ hybridization (FISH) detected a split signal (Figure  4 ). It is noteworthy that the low‐grade mucoepidermoid carcinoma (MEC) of the breast consists of basaloid cells, epidermoid cells, and mucous cells, and the MAML2 gene rearrangement was also found, these histological and molecular characteristics bear similarities to those of breast CCH, making their differential diagnosis challenging. However, the most distinctive histological feature of breast CCH is its glandular structures, which is not present in low‐grade MEC. Therefore, our final diagnosis was CCH of the breast. The patient recovered well 4 months after surgery, there was no tumor recurrence. Immunohistochemical staining showed the tumor cells highly expressed low‐molecular cytokeratins (Cam5.2) (a, ×400), CK14 (b, ×400), and p63 (c, ×400), but did not express calponin (f, ×400). The cuboidal cells were positive for SOX10 (d, ×400) but negative for p63 (black stars) (c, ×400). The basaloid and epidermal cells expressed CD117 (e, ×200). Dual‐color MAML2 Fluorescence in situ hybridization yielded break‐apart results: the orange signals and the green signals were split in the tumor cell nuclei (black arrows) (×600).

None declared.