Sebaceous breast carcinoma

ABSTRACT Breast sebaceous carcinoma is one of the rarest breast neoplasms, with less than 30 cases reported worldwide. Due to the rarity, the new WHO classification of breast tumors grouped these tumors among the ductal carcinoma. A detailed description of these cases is relevant due to the insufficient knowledge about the prognosis of this neoplasm. We report the clinical, histological, and immunohistochemical characteristics of a case of sebaceous carcinoma of the breast in an 81-year-old woman with a right breast nodule. The tumor was composed of nests of a varying mixture of sebaceous cells with abundant slightly vacuolated cytoplasm, surrounded by smaller oval-to-fusiform cells with eosinophilic cytoplasm without vacuolization. No lymph node metastases were present. The immunohistochemical reactions were positive for GATA3, EMA, CD15, and GCDFP15 (focal staining), and negative for RE, RP, and HER-2. The tumor was classified as triple-negative. Morphologically, the differential diagnoses included skin sebaceous carcinoma, lipid-rich carcinoma, apocrine carcinoma, and glycogen-rich clear cell carcinoma. Most of the previously reported cases were positive for RE and RP, which generally was associated with a better prognosis. However, some cases presented a more aggressive behavior with distant and lymph node metastases.


INTRODUCTION
The breast sebaceous carcinoma (SC) is a rare primary carcinoma with prominent sebaceous differentiation but without evidence of derivation from cutaneous adnexa. 1,2 Only a few cases have been reported; thus, the knowledge about the pathophysiology and prognosis is limited. 3 We report a case of breast sebaceous carcinoma and review the clinical, immunohistochemical, and histopathologic findings of previously reported cases.
A literature review was performed using the descriptors "sebaceous", "breast" and "carcinoma".
The following search platforms were used: Embase, Scielo, BVS, Pubmed, Google Scholar. Initially, 404 articles were found in Google Scholar, 257 in Embase, 1 in the BVS, and none in SciElo. Articles related to genetic research or description of sebaceous tumors from other locations were excluded. Due to the scant information, abstracts of case reports presented at congresses were also excluded. Some articles were indexed in two or more databases. Most of the selected articles were published in English, except for two of them. These were published in German and Spanish.
Finally, 25 well-described and well-documented case reports articles were selected. These articles contain reports of 27 cases of sebaceous breast carcinoma.

CASE REPORT
An 81-year-old black woman sought medical care after self-detection of a lump in her right breast. She denied alcoholism and smoking. History of hysterectomy for leiomyomatosis. Upon clinical examination, a 5.0 cm nodule was noted in the superomedial quadrant of the right breast. She underwent a biopsy five months later. Histopathological examination of the biopsy specimen revealed histological Nottingham grade II invasive ductal carcinoma of the breast. The delayed diagnosis was due to the patient's social and financial restraints.
Four months after the biopsy, she was referred to our hospital. The patient underwent segmental resection of the breast and sentinel lymph node and started adjuvant radiotherapy a month later. The analysis of the tissue sections showed a brownish firm-elastic tumor with well-defined margins, measuring 3.4 cm in its longest axis, and at a distance of 0.5 cm from the skin.
Histopathological examination revealed breast sebaceous carcinoma of Bloom and Richardson 4 grade III type (nuclear grade 3, histologic grade 3, mitotic grade 3) (Figure 1). A desmoplastic reaction was observed with mild inflammatory infiltrates, absence of angiolymphatic and perineural invasion, as well as the absence of metastatic disease in the examined sentinel lymph node. The pathologic staging was pT2 pN0 (TNM 8th edition).  The risks and benefits of an 81-year-old woman with other comorbidities were considered, and it was decided not to undergo adjuvant chemotherapy. Follow-up was conducted every three months for nine months.

DISCUSSION
Primary breast SC is rare and resembles skin sebaceous carcinoma. According to the current WHO classification, primary breast SC shows prominent sebaceous differentiation and no evidence of derivation from cutaneous adnexa. The previous WHO classification included the criterion that sebaceous differentiation occurs in at least 50% of cells. 1,2 Histologically, it is characterized by a lobulated or nested proliferation of a varying mixture of sebaceous cells with abundant, slightly vacuolated cytoplasm surrounded by smaller, oval to fusiform cells with eosinophilic cytoplasm without vacuolization. The nuclei of the sebaceous component are mainly located eccentrically and vary from small monomorphic cells to larger pleomorphic cells; mitotic figures may be abundant. 2 This was observed in our case ( Figure 1).
The differential diagnosis of breast SC includes skin sebaceous carcinoma, lipid-rich carcinoma, apocrine carcinoma, and glycogen-rich clear cell carcinoma. 1,3,5-7 The distinction of breast SC from skin SC can be made when there is no microscopic or macroscopic connection between the tumor and the overlying skin or when the tumor is surrounded by breast tissue. 3,8 In our case, there were no signs of skin involvement. The main characteristics of the other differential diagnoses are summarized in Table 1.
The origin of sebaceous cells in breast carcinoma is still unclear. The histogenic hypotheses include the existence of a ductal reserve cell capable of sebaceous differentiation and the displacement of an embryonic group of epidermal cells in the breast parenchyma. 5 To date, 27 well-documented cases have been reported in English, including ours. The clinical and pathologic characteristics observed in these cases are available in Table 2. Out of the cases in these reports, twenty-three patients were women with ages within 25 to 85 years and three were men aged between 55 and 70 years, the mean age being 60,3 years (53,08-67,52, IC 95%). Our patient's age was within the expected age range.

As shown in
The high ER and PR positivity rate in breast sebaceous carcinoma indicates that it is a hormone receptor-dependent breast cancer. 5 Based on hormone receptor state and HER2 expression, the number of cases of sebaceous breast cancer of the luminal, HER2positive, and triple-negative subtypes were thirteen, two, and five, respectively, which indicates that the luminal type is the most common subtype of breast SC and that this disease has a good prognosis and low invasiveness. 5 However, some cases exhibited a more aggressive lineage, with distant and lymph node metastases. 3,5,6,10,12,13 Our patient, unlike the majority of the described cases, was negative for ER, PR, and HER-2, and was therefore classified as triple-negative.
Positivity for GATA3 ( Figure 2B) and focal positivity for GCDFP15 ( Figure 2D) reinforced the breast origin of the tumor cells, and positivity for CD15 ( Figure 2C) confirmed sebaceous differentiation. Our case was the first described in the literature for which  CD15 immunostaining was performed; this marker was shown to be positive in skin sebaceous carcinomas. 26,27 We understand as the first description of sebaceous breast carcinoma the publication by Prescott RJ 9 of 1992. However, Bogaert and Madalgue 25 publication is cited as the first description. We find that the latter fits better the diagnosis of lipid-rich carcinoma due to sebaceous carcinoma. 25 Finally, the positive expression of the PMS2, MLH1, MSH2, and MSH6 proteins, used to detect microsatellite instability, permitted us to rule out the Muir-Torres syndrome, which is characterized by  the coexistence of sebaceous gland neoplasms and multiple visceral neoplasms. 8

CONCLUSION
We report a rare case of an 81-year-old woman with breast sebaceous carcinoma who, unlike what is expected for this subtype, was negative for RE, RP, and HER2. The tumor was thus classified as triplenegative, while most other reported cases had a high rate of positive expression of RE and RP and a low rate of positive expression of HER-2 and GCDFP-15. Our case is the first to be described in the literature, which had CD15 immunostaining performed, a positive marker in skin sebaceous carcinomas. Although breast sebaceous carcinomas are mostly of the luminal subtype, associated with a good prognosis, our analysis revealed cases that present a more aggressive lineage with distant and lymph node metastases. We conclude that the pathophysiology and prognosis of breast sebaceous carcinoma are poorly understood due to its rareness, and requires further study.