Low-Grade Adenosquamous Carcinoma of the Breast: A Case Report

Low-grade adenosquamous carcinoma (LGASC) of the breast is an uncommon type of carcinoma. It is categorized as a metaplastic carcinoma, but it differs from other cancers in this category by exhibiting a more favorable outcome. Because of its rarity and non-specific clinical and pathological features, LGASC of the breast continues to pose diagnostic challenges. The morphology of LGASC is characterized by the intimate admixture of well-developed glands and solid squamous cell nests within a fibrotic or cellular spindle stroma. A preoperative diagnosis is difficult to obtain from either fine-needle aspiration cytology or core needle biopsy because LGASC mimics benign tumors. We report the case of a patient with recurrent, apparently benign lesions which were repeatedly excised, who was finally diagnosed with LGASC after the third excision.

The patient was a 54-year-old female with a chief complaint of a lump in the left breast in 2018. Her past medical history revealed a history of surgery for mandibular cyst. Upon initial examination, palpation revealed an elastic soft lump measuring 4 cm in diameter. Mammography images showed an oval, circumscribed, equal density mass in the left lower outer quadrant. Ultrasound imaging revealed a 53 mm cystic lesion with internal solid components in the left outer region of the breast. Contrast-enhanced magnetic resonance imaging showed a tumor with solid components invading beyond the wall in the left CD area, raising the possibility of infiltrating ductal carcinoma (Fig. 1).

Ultrasound-guided core needle biopsy was performed for the left CD area tumor, and the pathologic diagnosis was papilloma with atypical ductal hyperplasia. Due to the possibility of malignancy based on imaging findings, excision of the breast tumor was performed. The pathologic characterization of the initial excised specimen yielded the diagnosis of intraductal papilloma with atypical ductal hyperplasia, coupled with negative surgical margins (Fig. 2).

The patient was followed up in the outpatient clinic, and an ultrasound examination in 2020 revealed a cystic tumor at the same location as the previous surgery, which exhibited an increasing trend in size (Fig. 3). Considering the recurrence of the benign lesion, this prompted the secondary excision of the breast tumor. Pathologic analysis of the second excised specimen identified the presence of ductal adenoma, with negative margins (Fig. 4).

With continuing follow-up in the outpatient clinic, a depression in the nipple was observed in 2022. Ultrasound findings revealed a cystic tumor near the left nipple. Contrast-enhanced magnetic resonance imaging revealed augmentation of a lesion within the left E area, fostering speculation regarding potential infiltration of contiguous breast tissue or the nipple (Fig. 5). Considering the recurrence of the benign lesion, we recommended the third excision of the breast tumor. However, based on the patient's preference, a left total mastectomy was performed (Fig. 6).

Pathologic diagnosis based on the excised specimen (Fig. 7): a tumor with an indistinct border extended around the cyst wall. Spindle-shaped or flattened tumor cells with enlarged nuclei formed cordate or vesicular foci. Some flat epithelial-like cells with abundant eosinophilic cytoplasm were present. The immunostaining demonstrated positivity in the tumor cells for myoepithelial markers (p63, CD10) and cytokeratin markers (CK AE1/3, CK5/6, CK 34βE12, CAM 5.2). These findings coalesced into the diagnosis of LGASC. The cyst wall was composed of different tumor cells, mainly short spindle-shaped tumor cells with slightly increased chromatin, accompanied by typical glandular components. The cyst resembled that observed in the previous specimen. The tissue was ER-negative, PR-negative, and HER2-negative, with a Ki-67 proliferation index of 9.8%, and was characterized by negative margins.

Postoperative course: according to the National Comprehensive Cancer Network (NCCN) guidelines, even in cases of ER-negative, PR-negative, HER2-negative LGASC, exclusive reliance upon localized therapeutic modalities is advised postoperatively. Following this principle, postoperative chemotherapy was not administered, and observation was continued. As of 20 months postoperatively, there has been no recurrence.

LGASC was first reported by Rosen et al. [1] in 1987 and is classified by the World Health Organization (WHO) as a type of metaplastic carcinoma. Lesions often appear on mammograms as irregularly shaped tumors with spiculation or calcifications, and as indistinct low-echo tumors on ultrasound images, although there are no specific characteristic features compared to other breast cancers. LGASC is difficult to diagnose through cytology or needle biopsy and can be misdiagnosed as fibroadenoma or sclerosing adenosis. In this case, we repeatedly excised in recurrence of the benign lesion, and finally diagnosed with LGASC after the third excision.

LGASC is often triple-negative but has a favorable prognosis due to its low-grade and indolent behavior. Larger tumor diameter increases the risk of metastasis, and complete excision with adequate margins is essential. The benefit of sentinel lymph node biopsy is debated due to the rarity of axillary lymph node metastasis; in this case, sentinel lymph node biopsy was not performed based on clinical findings.

A review of 32 cases was reported by Van Hoeven et al. [2] in 1993. In 13 of the reported cases, mastectomy was performed, in 19 patients a resection biopsy was performed, and 20 of the 25 patients who could be followed up had no recurrence, while 5 patients who underwent partial resection had local recurrence. Hormone receptors were negative in 13 of the 15 patients analyzed. Lymph node metastasis and lung metastasis were observed with tumor diameters of 8 cm and 3.5 cm. Among 32 cases of LGASC, 12 were thought to originate from intraductal papilloma.

The etiology of LGASC remains unclear, but there are reports suggesting that trauma, inflammation, or prolonged exposure to metal markers left during biopsy may induce squamous metaplasia during the reparative process of glandular epithelium, leading to cancer development [3]. On another finding, Lewis et al. analyzed 25 patients of LGASC about morphological and immunohistochemical characteristics. They showed that LGASC of the breast is frequently associated with other lesions, including complex sclerosing lesion/radial scar, fibroadenoma, intraductal adenoma, adenomyoepithelioma, phyllodes tumor, and carcinomas. They reported most commonly associated with intraductal papilloma, which presented in one-third of the cases [4]. In our case, the presence of LGASC near repeatedly excised benign lesions suggests the possibility of squamous metaplasia arising during the repair process from degeneration caused by surgical procedures, leading to cancer development.

Bataillon et al. analyzed 50 genes in 10 cases of LGASC, and found mutations in PIK3CA in 7 of the 10 cases, while none of the cases had mutations in TP53. Based on these findings of a high rate of PIK3CA mutations but no TP53 mutations, they speculated that LGASC exhibits an indolent progression and low grade of malignancy [5].

There is a lack of established evidence in favor of postoperative adjuvant chemotherapy, but there are numerous reports of cases treated without chemotherapy with no subsequent recurrence. According to NCCN guidelines, postoperative drug therapy including chemotherapy is unnecessary in cases showing triple-negative status. In the case reported here, in line with the NCCN guidelines, no postoperative chemotherapy was administered, and the patient was placed under observation. The necessity and specifics of adjuvant chemotherapy have not been established and reports of further cases are needed to determine diagnostic and treatment strategies.

We presented a case of low-grade adenosquamous breast carcinoma diagnosed postoperatively and managed without adjuvant treatment, showing no recurrence at 20 months postoperatively. LGASC is rare, and it has distinctive pathological features of the intimate admixture of well-developed glands and solid squamous cell nests within a fibrotic or cellular spindle stroma, but it is difficult to determine preoperatively with cytology or needle biopsy. LGASC is typically triple-negative. Surgery with a negative margin is necessary. Overall, LGASC has an indolent behavior. Adjuvant therapy after surgery is considered unnecessary for triple-negative status, but there is no clear evidence. Accumulation of further evidence is needed to refine diagnostic and therapeutic strategies of LGASC.

The authors thank NAI, Inc. for language editing.

The paper is exempt from ethical committee approval. This retrospective review of patient data did not require ethical approval in accordance with local/national guidelines. Written informed consent was obtained from the patient for publication of this case report and any accompanying images. The CARE Checklist has been completed by the authors for this case report, attached as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000542764).

The authors have no conflicts of interest to declare.

There were no sources of funding for this study.

R.O., H.S., Y.H., H.K., N.S., and M.I. treated this patient. R.O. wrote the manuscript. Y.I. and Y.A. reviewed and edited the manuscript. All authors contributed to discussions and agreed on the final version of the submitted manuscript.

All data generated or analyzed during this study are included in this article and its online supplementary material files. Further inquiries can be directed to the corresponding author.