Pleomorphic Lobular Carcinoma In Situ Composed of Signet-Ring Cells Mimicking Ductal Carcinoma In Situ with A Papillary Pattern: A Case Report

Introduction

Carcinoma with signet-ring cells consists of tumor cells with abundant intracellular mucin displacing the nuclei to the periphery creating the signet-ring cytomorphology. ¹ Signet-ring cells in the breast are further subclassified according to the distribution pattern of intracytoplasmic mucin. ² Mucin can be located within the large, intracytoplasmic lumina (also known as targetoid inclusion) or dispersed diffusely within the cytoplasm.

Although carcinoma with signet-ring cells is not a distinct entity in the World Health Organization (WHO) 2019 classification of breast carcinomas, ¹ primary signet-ring cell carcinoma is considered very rare and has unique biological behaviors. ³ Although the criteria for the diagnosis of signet-ring cell breast carcinoma have not been strictly defined, the presence of 20% or more signet-ring cells is commonly used.^4,5 Signet-ring cells can occur in pure intraepithelial proliferation, lobular carcinoma in situ (LCIS) or ductal carcinoma in situ (DCIS). ¹ Although it is common to find scattered signet-ring cells within classic LCIS,^6,7 signet-ring cells are rarely a prominent feature of pleomorphic LCIS. ⁸ To date, there are no well-established criteria for distinguishing classic LCIS with signet-ring cells from pleomorphic LCIS with signet-ring cells. In addition, it is not easy to distinguish pleomorphic LCIS from DCIS because pleomorphic LCIS consists of larger cells with marked nuclear pleomorphism.^1,9,10

Here, we report an interesting example of pleomorphic LCIS consisting predominantly of signet-ring cells with a papillary pattern mimicking DCIS. To our knowledge, no prior examples of pleomorphic LCIS composed predominantly of signet-ring cells with a papillary pattern have been described.

Case Report

A 58-year-old woman presented with a mass in the left breast detected by ultrasonography. Fourteen years previously, the patient underwent right breast-conserving surgery with lymph node dissection for invasive breast carcinoma of no special type. TNM staging was pT1bN0(sn). The tumor was negative for estrogen receptor (ER) and progesterone receptor (PR), but positive for human epidermal growth factor receptor 2 (HER2/neu) by immunohistochemistry. The patient received adjuvant chemotherapy and radiation therapy.

Ultrasonography revealed an irregular, parallel angular hypoechoic mass measuring 1.5 cm in the left 10 o’clock breast, which exhibited slow growth over the past two years. An ultrasound-guided core needle biopsy of the breast lesion was conducted. The tumor was composed of epithelial cells supported by a frond-forming fibrovascular stroma (Figure 1A). The space between fibrovascular stalks was filled with discohesive epithelial cells. The majority (> 70%) of the tumor cells displayed a signet-ring cell feature (Figure 1B). These tumor cells were pale stained and had diffuse voluminous intracytoplasmic content. Some of the nuclei of the signet-ring cells were round with intermediate-grade atypia. The signet-ring cells were admixed with more pleomorphic discohesive cells having prominent nucleoli (Figure 1C). Some of the pleomorphic discohesive cells appeared to be transitional forms with varying degrees of intracytoplasmic mucin. Mitotic activity was two mitotic figures/ten high-power fields. The fibrovascular stroma in some papillae was prominent as a result of the collagenization and collection of foamy histiocytes. Mucicarmine and PAS stains demonstrated intracytoplasmic mucin in the signet-ring cells (Figure 1D). E-cadherin immunohistochemistry was negative within the tumor cells, including the signet-ring cells, but highlighted the surrounding small myoepithelial cells, which were stained with p63 (Figure 2A, B). The signet-ring cells displayed positive immunoreactivity for HER2/neu (Figure 2C) and were negative for ER (Figure 2D) and PR. The Ki-67 labeling index was 30%.

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Figure 1.

Histopathological findings of pleomorphic lobular carcinoma in situ with signet-ring cells. (A) The tumor is composed of proliferation of discohesive epithelial cells supported by fibrovascular stroma (40×). (B) The vast majority of epithelial cells are signet-ring cells (200×). (C) Signet-ring cells were admixed with discohesive pleomorphic cells (400×). (D) Mucicarmine stain demonstrates intracytoplasmic mucin in signet-ring cells (200×).

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Figure 2.

Immunohistochemical findings of pleomorphic lobular carcinoma in situ with signet-ring cells. (A) Tumor cells including signet-ring cells show negative reaction for E-cadherin. Small myoepithelial cells show positive reaction (200×). (B) These myoepithelial cells are positive for p63 (200×). (C) Tumor cells display immunoreactivity for HER2/neu (200×). (D) Tumor cells are negative for estrogen receptor (200×).

A diagnosis of a pleomorphic LCIS with signet-ring cells was determined, and breast-conserving surgery was conducted. Invasive carcinoma and DCIS were not found in surgically resected specimens. Surgical margins were negative and the distance from LCIS to closest margin was 12 mm. Postoperatively, the patient received radiotherapy and remained disease-free after a follow-up of 26 months.

Discussion

Signet-ring cell carcinoma is a rare epithelial malignancy that produces mucin. ¹ The intracellular accumulation of mucin is probably related to the deletion of the enzymes necessary for mucin secretion. ¹¹ According to the most recent WHO classification of breast cancer, signet-ring cell carcinoma is not considered a separate entity because it lacks specific clinical or molecular features. ¹ Tumors reported in the literature for signet-ring cell carcinoma of the breast have variable proportions of signet-ring cells, and the presence of more than 20% of the tumor cells appearing as signet-ring cells is generally considered a requirement for the diagnosis of signet-ring cell breast carcinoma.^4,5 Signet-ring cytomorphology is common in lobular carcinoma and may also be present in ductal carcinoma but is rare in other special histologic subtypes. ¹ Pure signet-ring cell carcinoma of the breast is extremely rare. Wang et al recently reviewed 23 patients with pure signet-ring cell breast carcinoma and found that pure breast signet-ring cell carcinoma showed an aggressive behavior with a high level of lymph node metastasis, a high frequency of triple-negative breast cancer subtypes, and a high Ki-67 labeling index, leading to poor outcomes. ³ It is necessary to study more tumors to determine whether signet-ring cell carcinoma of the breasts is a subtype requiring aggressive management. The intraepithelial component associated with signet-ring cell carcinoma may be DCIS or LCIS.^3,11–13 Most of these intraepithelial components are of the conventional type, but signet-ring cells can also be seen within intraepithelial proliferation.^3,11–13

Kamiya et al subclassified the signet-ring cells in breast carcinoma into intracytoplasmic lumina and non-intracytoplasmic lumina types [2]. Intracytoplasmic lumina refers to intracytoplasmic vacuoles caused by intracellular mucin. ⁹ Non-intracytoplasmic lumina type corresponds to the signet-ring cell morphology observed in signet-ring cell carcinoma. Although non-intracytoplasmic lumina type signet-ring cells are common in ductal carcinoma and intracytoplasmic lumina-type signet-ring cells in lobular carcinoma, the origin of signet-ring cell carcinoma (ductal or lobular) cannot always be predicted by the features of the signet-ring cells. ²

Signet-ring cells can be seen in pure intraepithelial proliferation, LCIS or DCIS. ¹ Signet-ring cells are usually associated with classic LCIS,^6,7 but are rarely a prominent feature of pleomorphic LCIS. ⁸ Fadare reported a pure pleomorphic LCIS that was composed almost entirely of signet-ring cells and showed comedo-type necrosis. ⁸ Signet-ring cells are not common in DCIS and, if observed, frequently occur in solid papillary carcinoma. ¹ Solid papillary carcinoma is characterized by a solid growth pattern with delicate fibrovascular cores. Signet-ring cells have been identified in 2 of 19 tumors (10.5%), focally within the neoplastic proliferation. ¹⁴

Pleomorphic LCIS is composed of larger cells with marked nuclear pleomorphism, which are equivalent to high-grade DCIS.^1,9,10 A diagnosis of DCIS usually dictates surgical excision as definitive treatment. Management of LCIS varies depending on the type of lesion and different practices across the globe.^1,10 Pleomorphic LCIS does generally warrant more treatment. Most guidelines recommend surgical excision with clear margins. Unlike DCIS, appropriate margin clearance as well as the role of radiation therapy in pleomorphic LCIS is unclear.^1,10 Therefore, distinguishing DCIS from LCIS with signet-ring cells is clinically relevant, especially if signet-ring cells are identified in a core needle biopsy. Pleomorphic LCIS may be distinguished from DCIS by negative E-cadherin immunohistochemistry.^1,9,10 In addition, demonstrating the loss of membranous β-catenin and/or aberrant cytoplasmic p120 staining is supportive of a lobular phenotype.^1,9,10

Fisher et al described the potential mechanisms of LCIS having a papillary pattern. ¹⁵ The unfolding and invaginating of ductolobular unit into the lumen of a larger interlobular duct, resulting in so-called LCIS papilloma. Alternatively, the LCIS could have developed in a preexisting papilloma. In our patient, the tumor had fibrovascular stalks suggesting a papillary pattern in core needle biopsy specimens. The space between the fibrovascular stalks was filled with discohesive epithelial cells. The majority (> 70%) of the tumor cells showed a feature of non-intracytoplasmic lumina type signet-ring cells, which were mucicarmine positive. The signet-ring cells showed intermediate-grade nuclear atypia and were mixed with more pleomorphic discohesive cells with prominent nucleoli. The tumor cells, including the signet-ring cells, were negative for E-cadherin. The presence of a more conventional pleomorphic LCIS component and E-cadherin negativity suggests this is a pleomorphic LCIS predominantly comprised of signet-ring cells. Pleomorphic LCIS is ER-negative in 14–34% of tumors and shows HER2/neu overexpression in 13–43%.^1,9,10 Our tumor showed ER-negativity and HER2/neu overexpression. The Ki-67 labeling index was 30%.

In this patient, small myoepithelial cells highlighted by p63 appeared focally admixed with E-cadherin-negative LCIS cells, while the myoepithelial cells were positive for E-cadherin. Wang et al evaluated architectural and immunophenotypic alterations of LCIS-associated myoepithelial cells and recognized three patterns: pattern N (normal, flat against the basement membrane), pattern P (perpendicular to the basement membrane), and pattern C (central or nest-like). ¹⁶ Like the myoepithelial cells observed in this tumor, myoepithelial cells in pattern C appear focally admixed with LCIS cells. Pattern P and C architectural arrangements are relatively unique to LCIS.

LCIS is both a risk factor for and a non-obligate precursor of invasive breast carcinoma. Information about the natural history of pleomorphic LCIS is extremely limited. ¹ Approximately 25–60% of lesions with pleomorphic LCIS on a core biopsy are upgraded to carcinoma (including invasive carcinoma and DCIS) upon excision, and the WHO Classification of Tumour Editorial Board recommends excision for pleomorphic LCIS diagnosed by a core needle biopsy. ¹ After surgical excision, invasive carcinoma and DCIS were not observed in this patient.

The present report describes a rare pleomorphic LCIS that consists predominantly of signet-ring cells with a papillary pattern mimicking DCIS. To the author's knowledge, there have been no such case reports. Reports of additional examples with long-term follow-ups are needed to define the true natural history of these lesions.