Ductal carcinoma in-situ arising within benign phyllodes tumours: review of the literature and case presentation

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Case Report

Ductal carcinoma in-situ arising within benign phyllodes tumours: review of the literature and case presentation

https://doi.org/10.21203/rs.3.rs-4194574/v1

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INTRODUCTION: Phyllodes tumor (PT) is a rare benign tumor of the breast with a propensity to recur and metastasize. Ductal carcinoma in situ (DCIS) within PT is an extremely rare finding and is usually diagnosed postoperatively.

CASE PRESENTATION: We present a case of a 24-year-old female with bilateral multiple fibroadenomatosis and a growing lump in her right breast diagnosed as a atypical lobular hyperplasia. Preoperatively, surgical biopsy revealed DCIS within benign PT.

DISCUSSION: Phyllodes tumors are rare and ones with a coexisting carcinoma are even less frequently encountered. No standard management protocol exists for such cases, but when detected by histopathology, the clinical management and prognosis have to undergo a complete change. Treatment should be guided by the type and stage of carcinoma detected and proper individualized management by a multidisciplinary team play a crucial role.

CONCLUSION: Phyllodes tumors are rare and ones with a coexisting carcinoma are even less frequently encountered. No standard management protocol exists for such cases, but when detected by histopathology, the clinical management and prognosis have to undergo a complete change. Preoperative diagnosis and proper individualized management by a multidisciplinary team that ensures clear surgical margins and planned adjuvant therapy or close follow up play a crucial role in preventing the recurrence of DCIS within PT.

Ductal carcinoma in-situ

phyllodes tumors

breast cancer

case-report

Phyllodes tumors are fibroepithelial breast tumors; they account for less than 1% of all breast cancer. Phyllodes tumours have characteristic epithelial components arranged in clefts, surrounded by a mesenchymal component organized in a leaflike pattern. Although malignant transformation of the stromal component can occur, a carcinoma arising from the epithelial component is only rarely reported. To date, 19 cases of DCIS arising from phyllodes tumors have been reported. We present a review and a case discussion of a 24-year-old woman diagnosed with DCIS arising from a phyllodes tumor, who was managed with oncoplastic breast conserving surgery.

We present a case of a 24-year-old female on regular ultrasound follow-up for bilateral multiple fibroadenomatosis. The annual follow-up ultrasound scan of the upper-outer quadrant of the right breast documented a volumetric increase of the previously described oval nodule of about 22 mm (versus 16 mm in the previous control). (Fig. 1) Given the volumetric increase, it was decided to type it with biopsy: the morphological picture and the result of immunohistochemical investigations raised the suspicion for the presence of an atypical lobular epithelial proliferation (atypical lobular hyperplasia) in the context of a fibroepithelial lesion of the breast. (B3 lesion according to European Guidelines).

Once the case had been discussed collectively, an indication was given to exeresis of this formation. Histological examination showed Grade 1 and 2 sec. WHO solid architecture and cribriform intraductal carcinoma, arising in the context of a benign phyllodes tumor of the breast, without evidence of stromal infiltration. The intraductal cancer is < 1 mm from the resection margin. Grading G1-2, ER > 95%, PgR > 95%, Ki-67: 5%.

The macroscopic examination demonstrated a well circumscribed mass, with yellowish-grey cut surface and a taut-elastic consistency. The lesion measured 22 mm in maximal dimension and was clear from the resection margins (with minimum distance < 1mm).

Histological sections showed a biphasic fibroepithelial neoplasm with leaf-like epithelial (phyllodal) pattern and stromal proliferation of monomorphic spindle cells with no or minimal atypia without any heterologous stromal differentiation. Stromal mitoses were rare (0–1 mitoses/mm2) and there was no evidence of stromal overgrowth. (Fig. 2)

Inside this lesion, some areas of the epithelial component showed outspoken malignant features. In these areas, the phyllodal epithelium was distended and completely filled by relatively uniform, round, small-to-medium sized cells. The cells had well-defined cell boundaries and showed polarization around solid and cribriform structures. Mitoses were sparse, chromatin was usually finely dispersed, and nucleoli were not prominent.

These areas definitely displayed features of ductal carcinoma in situ (DCIS) without any features of stromal invasion. DCIS component had a maximus extension of 20 mm. (Fig. 3)

Considering the patient's clinic radiological profile and the histopathological findings, the diagnosis was DCIS (grade 1 and 2 according to WHO) arising in a case of benign PT.

The patient was then subjected to surgical enlargement of the previous surgery on the right breast, after performing breast MRI, which led to the complete removal of the neoformation previously described. Histological examination was free of residual cancer.

In consideration of the presence of low-grading DCIS for the patient, from an oncological point of view, only close follow-up was indicated, in consideration of the low-risk characteristics of the DCIS, the oncological history and the possible side effects. After one year of follow up, ultrasound and mammography does not show any elements of suspicion (BI-RADS2).

Lui et al. conducted a research of published data on carcinomas arising within phyllodes tumours and they found Only 41 cases of carcinoma arising in patients with phyllodes tumours were identified, of which 19 were DCIS [16]. Of the 19 cases with DCIS, all were female, with ages ranging from 23 to 80 years. Six arose from malignant phyllodes tumours, two from borderline phyllodes tumours and ten from benign phyllodes tumours. However, among the ten cases, only six had pure DCIS from benign phyllodes tumours, ours being the first case to be reported in the Italian literature. The size of the phyllodes tumours ranged widely between 2.0 cm and 21.0 cm, suggesting that DCIS can occur in any palpable phyllodes tumor. Eight cases underwent wide local excision while the rest underwent total mastectomy. Apart from four cases of DCIS with invasive components, the remainder of the patients with DCIS had negative lymph node involvement or did not undergo axillary lymph nodal sampling or dissection. Stromal overgrowth has been reported with rapidly enlarging phyllodes tumours; epithelial hyperplasia has also been reported to occur in as high as 74% of phyllodes tumours [17]. The best-practice diagnostic guidelines published by the Cancer Reform Strategy Breast Cancer Working Group does not recommend biopsy in women younger than 25 years of age with ultrasound showing typical features of fibroadenoma [18]. In our patient, however, the clinically rapidly enlarging size and heterogenicity of the lesion on ultrasound were suspicious, hence a biopsy was performed. Standard treatment for phyllodes tumours involves surgical resection with no need for axillary sampling or dissection. However, adjuvant therapy may be indicated for patients with epithelial malignant change, be it radiotherapy, chemotherapy or endocrine therapy. Patients with DCIS who have had breast-conserving surgery are typically offered adjuvant radiotherapy to reduce local recurrence rates. Young age at diagnosis has been reported to be an independent predictor for local recurrence even after controlling for factors such as tumor size, presence of comedo-necrosis and clinical presentation [19–20]. A local study by Tan et al. showed a local recurrence rate of 10.9% for benign phyllodes tumours with no distant metastases [21]. From this study, the predicted recurrence-free survival is more than 0.95 at 10 years for our patient. According to another validated normogram published in the Journal of Clinical Oncology in 2010 for the Western population, the ipsilateral breast tumor recurrence rate is about 0.2 at 10 years [22]. Based on the University of South California/Van Nuys Prognostic Index, our patient had intermediate-risk DCIS. A 2008 study by Di Saverio showed a 10-year disease-free survival of 86.8% for patients who underwent radiotherapy and 78.5% for those who did not, although this was not significant [23]. Interestingly, a more recent study by Kim et al. showed that patients with intermediate risk DCIS who did not undergo radiotherapy had no recurrence [24]. Fortunately, a 2015 analysis assessing 20-year mortality outcomes in patients with DCIS demonstrated no survival benefit to radiation, although it did reduce local recurrence risks significantly.

Phyllodes tumors are further divided into three groups of benign, borderline or malignant tumors according to the World Health Organization (WHO) 2012 classification [1, 2, 4, 6–8, 12]. The diagnostic criteria are also based on similar criteria for the initial diagnosis: stromal overgrowth, hypercellularity, atypia, high mitosis rate, infiltrative borders and the presence of necrosis. The malignancy potential is based on a large tumor size (> 4 cm in diameter), the loss of defined margins and more infiltrative borders, more cellular atypia and increased mitotic activity [3, 11]. More detailed diagnostic differentiation is used for this subdivision. For example, a mitotic rate of less than 5 per 10 high power field (HPF) suggests “benign” subdivision, between 5–10 HPF “borderline”, and more than 10 per 10 HPF “malignancy” [6]. In the literature, the histologic distribution of phyllodes tumors into benign, borderline, and malignant is 54–58 percent, 12 percent, and 30–33 percent, respectively [14, 15].

When a coexisting carcinoma arises, the distinction becomes challenging [2, 7, 11]. Although extremely rare, all subdivisions of phyllodes tumor can harbor carcinomas. These carcinomas can be carried in two forms; either present as a separate lesion in the ipsilateral or contralateral breast; or inhabiting within the phyllodes tumor itself [4–7]. Different kinds of carcinomas were reported in the literature: DCIS, tubular carcinoma, invasive ductal /lobular carcinoma, and squamous cell carcinoma [6, 8]. One diagnostic challenge of coexisting carcinoma with phyllodes is to differentiate from the carcinosarcoma—a subtype of metaplastic carcinoma. By WHO classification, the differentiation of carcinosarcoma is the presence of both epithelial and mesenchymal components, with mesenchymal component showing malignant microscopic features without epithelial makers. Nonetheless, it remains a diagnostic challenge [2, 7, 11].

Phyllodes tumors occur within a wide age distribution ranging from the 2nd to the 6th decade of life [1, 2]. Patients who have coexisting carcinoma with phyllodes are more likely to be older than 50 years of age [4, 6]. However, there have been several reported cases of young patients in their 20–30 s with coexisting DCIS. Our reported patient cases follow a similar young age of diagnosis. Additionally, the age distribution follows a pattern of ethnic predilection, with Asian females with phyllodes tumors diagnosed at a younger age compared to Caucasian females [1, 2, 8, 11]. In the Bernstein et al study done in Los Angeles in1993, Asian and Latina’s patients were significantly younger than non-Latina white patients. Similarly, in the Panda et al study in 2016, phyllodes tumors found in Asian countries occurred primarily in the 25–30-year age group and accounted for a higher proportion of primary breast tumors. Both of our patients were born in China and came to the US at a later age. The exact genetic and environmental contributing factors to this variation are unknown.

Surgery has been viewed as the primary treatment for phyllodes tumors [2, 6, 7]. The options are a lumpectomy versus a mastectomy. The main determining factor is the size of the mass, the breast size and the acceptable cosmetic outcome. Once the surgical choice has been made, the question of margin arises. Wide local excision of the tumor with negative margins results in 90% local control rate and is recommended when cosmetic appearance is acceptable [2]. However, the exact margin length is controversial. The current National Comprehensive Cancer Network (NCCN) guidelines for the management of phyllodes tumors recommends wide excision with margins ≥ 1 cm and recommends against axillary staging [9, 10]. However, in recent years, a smaller margin for benign phyllodes tumors has been discussed and has started to gain popularity. In Moutte et al study in 2016, 77 patients were reviewed and identified small negative surgical margins: <10 mm in 89%. Re-excision was not performed and there was no increase in the local recurrence rate (4%) observed when compared to recurrence rates over 58 months follow up. Thus, they recommended against re-excision for benign phyllodes with close or positive surgical margins to achieve margins beyond 1 cm. Regardless of the margin, regular clinical and imaging follow-up is highly recommended, as most recurrences happen during the first two years of the initial surgery.

Although challenging, the detection of a carcinoma component in phyllodes tumor is important, as it can dictate the need for lymph node sampling and possible adjuvant therapies such as radiation and systemic management [6]. The current NCCN guideline recommends against lymph node sampling for isolated phyllodes, as malignant phyllodes tumors more commonly spread via a hematogenous route and lymphatic metastases are extremely rare [6, 7, 13]. In the case of a coexisting carcinoma, which is often diagnosed only after the excision, the treatment plan can change [6–9, 14].

Routine use of radiation is not recommended for phyllodes tumors as there are no randomized studies supporting the use of post-operative radiation. An exception is when local recurrence would result in significant morbidity at which point radiation therapy is considered following a sarcoma treatment protocol [9].

Despite the generally favorable prognosis of phyllodes,13–20% of patients with malignant phyllodes experience distant metastasis within10 years. No standard chemotherapy is currently recommended [6, 7]. Malignant phyllodes tumors tend to be more aggressive and have a higher chance of metastasis, however, metastases have been reported in up to 8% of initially histologically benign tumors in a 10-year period [6]. Although stromal overgrowth is the strongest predictor of distant metastasis, it is hard to predict. Local failure rates for benign tumors range between 5–15% and 20–30% for malignant tumors [2, 7].

Phyllodes tumors are rare and ones with a coexisting carcinoma are even less frequently encountered. No standard management protocol exists for such cases, but when detected by histopathology, the clinical management and prognosis have to undergo a complete change. Preoperative diagnosis and proper individualized management by a multidisciplinary team that ensures clear surgical margins and planned adjuvant therapy or close follow up play a crucial role in preventing the recurrence of DCIS within PT.

Conflicts of interest

The authors declare that they have no conflict of interest.

Sources of funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Ethical approval

No research ethics approval was necessary for this case report.

Consent

Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.

Author Contribution

DEGUIDI GIULIA: study conception, acquisition of data, writing, reviewing and editingNOTTEGAR ALESSIA: study conception, acquisition of data, writing, reviewing and editingBARILLARI MARCO: study conception, acquisition of data, writing, reviewing and editingFIORINI DENISE: writing, reviewing and editingMIRANDOLA SARA: reviewing and editingINVENTO ALESSANDRA: reviewing and editingCALDANA MARINA: reviewing and editingTOMBOLAN VALERIA: reviewing and editingBERTOLDI LORENZO: study conception, acquisition of data, writing, reviewing and editingBOSIO GIACOMO: reviewing and editingPELLINI FRANCESCA: study conception, acquisition of data, writing, reviewing and editingAll authors read and approved the final manuscript.

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No competing interests reported.

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Ductal carcinoma in-situ arising within benign phyllodes tumours: review of the literature and case presentation

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INTRODUCTION

CASE PRESENTATION AND REVIEW OF THE LITERATURE

DISCUSSION

CONCLUSION

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Author Contribution

References

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