Pancreatic metastases and first reported gallbladder metastasis from phyllodes tumor of the breast

Highlights

Introduction

Phyllodes tumors of the breast are rare and usually benign. They are graded as benign, borderline or malignant based on the World Health Organisation (WHO) classification, according to a constellation of five histologic parameters. Metastases are very rare: The overall rates of distant metastases in PTs range from 1.7% to 27.1%, with an average of 5.6%, and vary according to tumor grade. ¹ They usually occur in lung and bones. Predictive factors of malignancy of phyllodes tumor of the breast are size, mitotic index, stromal atypia, overgrowth, surgical margins, ¹ and expression of CD117. ²

We report a case of very aggressive phyllodes tumor of the breast that metastasized in lung, brain and in unusual sites: pancreas and gallbladder.

While most invasive primary breast cancers are epithelial derived adenocarcinomas, rare neoplasms such as phyllodes tumor may arise from mesenchymal tissue. Phyllodes tumors represent 0.3% to 1.0% of the entire mammary tumors. ³ Cystosarcoma phyllodes was first described in 1838 and was originally considered to be a benign tumor until 1931 when metastasis from a cystosarcoma phyllodes was reported for the first time. ³ In fact, fibro-epithelial breast neoplasms exhibit a spectrum of clinical behavior ranging from benign tumors, which may be indistinguishable from fibroadenomas and may be healed by local surgery, to aggressive malignant tumors which have a propensity for rapid growth metastatic spread. ⁴ Pancreatic metastases from breast phyllodes tumors have rarely been reported in the literature, typical sites of the metastases being lungs and bones. ⁴ This case enriches the literature with another example of pancreatic metastasis of phyllodes tumor. We also report, for the first time in the literature, gallbladder metastasis from phyllodes tumor.

Case observation

A nulliparous woman aged 51 years old was hospitalized in our general surgical department for atypical epigastric pain associated with some vomiting episodes. Her medical history started 3 years ago when a mammogram was performed and the found lesion was considered a fibroadenoma. One year later, a second mammogram showed an increase in tumor size measuring 4 × 5 × 6 cm. She had a left mastectomy. Pathological and immunohistochemical examination of the specimen showed that it was phyllodes tumor with highly cellular and diffuse proliferation of malignant mesenchymal round and spindle cells, displaying marked nuclear atypia and mitotic figures, focally surrounding a residual acinar stricture. Cells expressed Vimentin, but not CKs or neuroendocrine markers. CD117, CD99, and TTF1 were negative. Surgical margins were satisfactory. The tumor was considered malignant. A full-body CT scan was performed which didn’t show the presence of secondary lesions.

Two months after surgery, she underwent adjuvant radiotherapy of the chest wall on the site of mastectomy. She received a 52.2 Gy spread over 2 months at a rate of 1.8 Gy per fraction and 5 fractions per week.

The patient was followed at the outpatient clinic with a clinical examination every 3 months and a full-body CT scan at 6 months, which suddenly showed 5.5 cm metastatic pulmonary nodule. She had left upper pulmonary lobectomy with ganglionic lymphadenectomy. The metastatic nature of this nodule was confirmed with its histopathological examination. Surgical margins were satisfactory.

The patient was followed up with a clinical examination every 3 months and a full-body CT scan every 6 months. Two years after mastectomy, about 18 months after pulmonary metastasis surgery, she complained of abdominal pain mimicking pancreatitis pain leading to her hospitalization in the surgical department.

Abdominal CT scan showed solid exophytic pancreatic masses of 56 and 33 mm longer axe each one, with no signs of vascular, lymphatic or neighboring organs spread (Figure 1).

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Figure 1.

CT scan: pancreatic metastasis of phyllodes tumor.

The diagnostic dilemma was whether this was a case of primary pancreatic cancer or a recurrent phyllodes tumor presenting as pancreatic metastasis, which is very rare. In this context of two pancreatic metastatic localizations (corporeal and caudal), we have concluded to pancreatic metastases.

Radical surgery was indicated to that resectable pancreatic tumor in a good general condition patient. Therefore, she had laparoscopic splenopancreatectomy and she needed cuneiform resection of the stomach because it was adhering to the tumor.

Histological examination confirmed that it was pancreatic tumor metastases of her breast phyllodes tumor. Macroscopically, we found two metastatic pancreatic oval whitish masses both of 7 cm on their large diameter, well limited, rearranged by necrosis and hemorrhage, and separated by normal pancreatic tissue. Lesions were rich in blood vessels. Cells expressed Vimentin, but not CKs (CK7−, CK20−, CK19−). There was also no expression of neuroendocrine markers, of CD117, of CD99 and of TTF1. Surgical pancreatic margins were satisfactory. The spleen and the resected gastric part were not infiltrated by tumor (Figure 2).

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Figure 2.

Immunohistochemical examination of the specimen.

Chemotherapy based on doxorubicin and cyclophosphamide was indicated. Three months after the last surgery, a new CT scan showed a bulging mass in the gallbladder that 3 months ago did not exist on previous computed tomography imaging (Figure 3). We concluded that this was a new metastasis of her aggressive phyllodes tumor.

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Figure 3.

CT scan: metastasis in gallbladder.

A whole body MRI has been conducted and has revealed two asymptomatic cerebral metastatic lesions. The patient died 5 weeks later.

Discussion

Phyllodes tumors of the breast are infrequently encountered fibroepithelial neoplasms, comprising 0.3% to 1.0% of all primary breast tumors in Western countries. ¹ Most phyllodes tumors occur in women between the ages of 35 and 55 years old, ⁴ and according to Surveillance, Epidemiology, and End Results (SEER) data, the median age at diagnosis of women is 50 years.

Phyllodes tumors were further classified as benign, borderline, or malignant on the basis of features of the stromal cells. About 10% to 20% of those tumors are classified as malignant. ³ Traditionally, predictors of malignant behavior include tumor size, cytological atypia, mitotic rate, tumor necrosis, stromal atypia, overgrowth, surgical margins.^1,3,5 Malignant phyllodes tumors are diagnosed when there are marked stromal hypercellularity, atypia, increased mitoses of ⩾10/10 HPFs, permeative tumor borders, and stromal overgrowth. The presence of a malignant heterologous component places the tumor into the malignant category regardless of other histological features. ⁶

Most recently, expression of CD117 (KIT) was shown to be associated with unfavorable pathologic criteria and worse prognosis in patients with phyllodes tumor, although no mutation in the CD117 gene has been identified. ²

Treatment of phyllodes tumor is remaining primarily surgical. Nonsurgical therapies are still controversial and uncertain. Neoadjuvant treatment was reported in one isolated case, with the patient demonstrating no response after three cycles of doxorubicin prior to surgical resection. ⁷ The role of adjuvant radiotherapy was demonstrated for high-risk phyllodes tumors.^8,9 The National Comprehensive Cancer Network (NCCN) suggested radiation therapy for local recurrence, but it did not prevent distant metastasis and had no effect on disease-free survival or overall survival.

The real question was whether we should systematically indicate adjuvant chemotherapy for patients that gather all high-risk phyllodes tumor criteria or not. In a study of 101 patients with phyllodes tumor, of whom four received adjuvant chemotherapy, the authors suggested that adjuvant chemotherapy should be considered in patients with stromal over-growth. ¹⁰ But according to many other studies, there was no established role for adjuvant chemotherapy in phyllodes tumors.^6,11,12

The overall metastatic rate of phyllodes tumor in general has been reported at <5%. ¹² Tumor size, stromal atypia, mitotic activity, local recurrence and surgical excision margin have been described as predictors for developing distant metastasis.^4,11 Malignant phyllodes tumor is not a particularly lethal neoplasm when resected, but average survival time of patients with phyllodes tumor metastasis was reported to be at 30 months. ¹²

Metastases to the pancreas from phyllodes tumor are extremely rare. A comprehensive review of the literature identified only seven case reports.^13–19 Among the four resected cases of pancreatic metastasis,^15–18 two cases showed early relapse;^16,17 whereas one patient survived for a long time after resection. ¹⁴

Gallbladder metastasis of phyllodes tumor has never been described before in the literature. In this case, it was a proof of that special tumor aggressiveness and it suggested its spread through biliary tract, because it happened after pancreatic metastasis.

However, initial histological findings were not suggesting that high grade of malignancy, when they specially revealed absence of CD117 expression, which is known to be associated with worse prognosis. ²

Complete surgical removal of the involved pancreatic metastatic site is benefic, but when new metastases appear in a short time, systemic treatment should be considered early. Chemotherapy that includes ifosfamide was reported to be effective. ¹⁰ More pooling of data may be beneficial to identify specific findings that increase pre-test probability, prior to making a decision whether to treat systemically the metastatic mass or to proceed to surgery.

Conclusion

Malignant phyllodes tumor of the breast is an unpredictable and sometimes very aggressive neoplasm. Stromal overgrowth in malignant phyllodes tumor carries a severe prognosis. Adjuvant treatment for phyllodes tumor is currently limited to radiation therapy as chemotherapeutic intervention is consistently proven ineffective. Genomic-level research performed on resected phyllodes tumors has the potential to identify novel drug targets in the future. Current guidelines from the NCCN indicate that malignant phyllodes tumor should be treated as sarcomas rather than typical breast carcinomas.