Malignant Phyllodes Tumor With Metastases to the Femur the Lung and Bilateral Axillas: A Case Report and Review of Literature

Background: Phyllodes tumor is rare accounting for <1% of all breast tumors. It is classied as benign, borderline, or malignant.The lymph node is involved rarely, and the most common metastasis path is through hematogenous channels mainly to the lung the pleura and the bone. Case presentation: This case report presents a 34-year-old woman suffered from metastases to the femur the lung and bilateral axillas from a malignant phyllodes tumor in 9 years. The most recent recurrence was discovered on bilateral axillas. The patient accepted adjuvant chemotherapy. However, because no obvious benet of chemotherapy was found, the patient received bilateral axillary lymph node dissection nally. Genetic testing after surgery showed tumor-specic mutations and mutations about thepolymorphism of drug metabolism-related enzymes. Conclusions: The primary treatment modality for phyllodes tumor is surgery. For metastases, adjuvant chemotherapy may be ecient. However, when the effect of chemotherapy is not obvious, aggressive surgical therapies should be performed. Besides, genetic testing can provide advices on effective treatments. testing results indicated the tumor cells were more sensitive to platinum drugs, uorouracil drugs and anthracyclines and the toxic effects of irinotecan etoposide methotrexate and uorouracil drugs would increase. However the sensitivity of tumor cells to targeted agents, immunotherapy and inhibitors of poly-ADP-ribose polymerase(PARP) was not affected by the gene mutations.


Introduction
Phyllodes tumor (PT) is a rare type of breast tumor accounting for < 1% of all breast tumors. [1]They are classi ed by the World Health Organization (WHO) into benign, borderline and malignant variants. It usually occurs in middle-aged women, mostly 35-55 years old. [2] Clinically, the size of PT is 4-7 cm on average, [3] only less than 10% of PTs can grow larger than 10 cm. [4]The lymph node is involved rarely, and the most common metastasis path is through hematogenous channels, mainly to the lung the pleura and the bone. [5] Herein, we report a patient with metastases to the femur the lung and bilateral axillas from a malignant phyllodes tumor of the breast and review literature about PT.

Case Presentation
In November 2019, a 34-year-old married premenopausal female was admitted into the department of thyroid and breast surgery of our hospital with a 3-month history of multiple lumps in bilateral axillas. There was no history of similar illness in rst degree relatives. The patient attained menarche at the age of 16 years old. She is a non-smoker and denies history of alcohol intake.
On examination in our department, multiple lumps occupying bilateral axillas was observed. The largest lump in the right axilla was about 2*1CM and the largest lump in the left axilla was about 3*2CM. All of the lumps had clear margin, rubbery consistency and had no spontaneous pain or tenderness.
On investigating the patient, ultrasound showed multiple lumps in bilateral axillas ,which were considered metastatic tumors (Fig. 1). A chest computed tomography (CT) showed no abnormality and whole body bone scan showed no evidence of metastasis. Needle aspiration biopsy of the lumps revealed borderline Page 3/13 or malignant phyllodes tumors. Mammary tissue and actively proliferous stromal cells was found in the lump of the right axilla and proliferous spindle cells was found in the lump of the left axilla (Fig. 2). 9 years ago, the patient discovered a mass about 8*6cm in her right breast for which she got admitted in our department. Then a lumpectomy was conducted. Histopathological examination showed it was a malignant phyllodes tumor. (supplementary material 1) Immunohistochemical stains showed ER(-), Her-2(-),PR(-),AE1/AE3(-),Vimentin(+),a-SMA(-/+),colponin(-),S-100(-/+)CD34(partially+),P53(-/+),Ki67(30%-40%+). The tumor reappeared within 9 months with a size of 11*8cm in upper inner and lower inner quadrants of her right breast. Then a needle aspiration biopsy was conducted, histopathological examination showed tumor cells according with typical malignant phyllodes tumor cells and no evidence of metastasis to axillary lymph nodes. Therefore, with the agreement of the patient a mastectomy was conducted in Fudan University Shanghai Cancer Center .Histopathological examination showed a typical representation of malignant phyllodes tumor. Combining with the history, our team recommend the patient to receive adjuvant chemotherapy. Adjuvant chemotherapy with doxorubicin liposome (35mg/m2 administered intravenously push on day 1) plus isophosphamide (1.2-2.0g/m2 administered intravenously push on days1-3) was planned for 1 cycle every 3 weeks. Bilateral axillary ultrasound were performed to evaluate the response to chemotherapy every cycle. When the patient compeleted 4 cycles of adjuvant chemotherapy ,the ultrasound examination to super cial lymph nodes revealed that the largest lump in the right axilla had decreased to 1*1CM and the largest lump in the left axilla had increased to 3*3CM.
In January 2020,the patient presented in our hospital for right atrial thrombus and received anticoagulation treatment. As the effect of adjuvant chemotherapy was not evident, in march 2020, after the anticoagulation treatment nished the patient received bilateral axillary lymph node dissection.
( Fig. 3) The mass excised in the right axilla was about 1*1CM and the mass excised in the left axilla was about 3*3 CM, both of the masses had the characteristics of hard, clear boundary, oval shape and shy texture. Histopathological examination showed spindle cells proliferated in the lumps excised from bilateral axillas and moderate dysplasia of the spindle cells form intercellular substance. The mitoses are common (> 10/10HPF) and stromal cells proliferate actively. (Fig. 4) Combining with the medical history the lumps were considered as borderline or malignant phyllodes tumors. Immunohistochemical stains showed CD34(+), CD68(+), Desmin(-), Ki67(20%), VIM(+++). The disease progression is shown in Fig. 5.
After bilateral axillary lymph node dissection, a genetic testing for all types of cancers was conducted.
The testing covered 425 genes with a total of 1.28Mb of nucleotide sites, exons, fusion related introns, variable shear regions and the speci c microsatellite loci of the genes were included. (supplementary material 2) The testing results included the information of point mutations in the coverage area, small fragment insertion and deletion mutations, gene fusion and copy number variation, the analytical results of icrosatellite and the information of tumor mutation burden (TMB). Tumor-speci c mutations which can leads to tumorigenesis and the development of the tumor were displayed in the testing results . (Table1)The gene mutations about the polymorphism of drug metabolism-related enzymes were also found. (Table 2)However, no mutations about mismatch repair genes and germline genes were found and no microsatellite instability (MSI) was found. Besides the tumor mutation burden was 5.7mutations /Mb. The testing results indicated the tumor cells were more sensitive to platinum drugs, uorouracil drugs and anthracyclines and the toxic effects of irinotecan etoposide methotrexate and uorouracil drugs would increase. However the sensitivity of tumor cells to targeted agents, immunotherapy and inhibitors of poly-ADP-ribose polymerase(PARP) was not affected by the gene mutations. Note: the abundance of mutation is de ned as the speci c percentage of mutant alleles in a locus  PTs have long medical history ranged from several months to years and the early performances of PT are not typical . [19]The tumor always be found in a unilateral breast and with the characteristics of hard, clear boundary, oval or phyllodes shape, good tumor mobility, and non-adherence to skin. [5]Clinically, the size of PT is 4-7 cm on average. [3]Only less than 10% of PTs can grow larger than 10 cm. A case report by Islam et al showed a phyllodes tumor with the size of 50 × 50 cm which is the largest one up till now. [4]Huge mass can result in ulcerated, thinned, and tightened skin. The lymph node is involved rarely, and the most common metastasis path is through hematogenous channels, mainly to the lung, the pleura, and the bone. The presence of metastatic disease usually indicates a bleak prognosis followed by death soon after with no long term survivors. [5,20]As to this case, the patient has a long history of up to 9 years and had experienced metastases to the femur the lung and bilateral axillas. Preoperative diagnosis of breast PT is di cult. Ultrasound and mammography usually show an unfeatured picture with large, round or lobulated masses with clear boundary. Whereas, some studies found diagnostic differences in magnetic resonance imaging(MRI): the enhancement curve of benign PT was almost ascending type and that of malignant tumor was at or platform type. [21]Pathological examination is the gold standard in the diagnosis of PT .Core needle biopsy has been widely applied with a accuracy rate as high as 99%, and the positive predictive value and negative predictive value are 93% and 83%.However, the false negative predictive value is 39%. [22] Therefore the de nite diagnosis still depends on the complete excision of the tumor. In this case ultrasound showed a typical picture with multiple round lumps with clear boundary in bilateral axillas and needle aspiration biopsy of the lumps revealed borderline or malignant phyllodes tumors. The basic treatment modality for this cancer is surgery including various operation methods such as lumpectomy, wide local excision, and total mastectomy. A study revealed that radical surgery do improve the survival and decreased the rate of local recurrence. [23]The study by Tan et al indicated that the state of surgical margin was an important prognostic factor. [24]The National Comprehensive Cancer Network recommends that the range of negative margin should be more than 1 cm. However, securing a su cient margin is di cult in most cases because of huge tumor sizes that can occupy the entire breast. In such cases a complete mastectomy is often needed. [25]The absence of skin requires extensive removal during surgery. Besides, some think that due to high recurrence rate in malignant subgroup, as long as the histopathological diagnosis was malignance before or during operation, all patients should undergo total mastectomy regardless of the tumor size.
[26]Lymph node is barely involved in PTs, so routine axillary lymph node dissection is often unnecessary, unless lymph node involvement has been diagnosed pathologically. [10] The effect of postoperative comprehensive treatments such as adjuvant chemotherapy against malignant PT is still unclear. For metastatic malignant phyllodes tumors, Ifosfamide may be a active agent [27].Doxorubicin and dacarbazine have been reported to be effective when combined with cisplatin or ifosfamide.
[28]Besides postoperative radiotherapy does not improve prognosis regardless of type of surgery. [29]On the other hand, a reported by Belkacemi et al showed that radiotherapy decreased local recurrence in malignant PT and borderline PTs at 10 years but did not affect overall survival. [30]58% and 75% of PT has been reported as ER(+) and PR(+) but no de ned bene t has been derived from hormone therapy. [31]The patient underwent surgeries several times in 9 years. However no obvious bene t was found. Therefore adjuvant chemotherapy with doxorubicin liposome plus isophosphamide was recommended. However, because of ine cient of the adjuvant chemotherapy, the patient nally received bilateral axillary lymph node dissection. After this, the patient received genetic testing, and it was showed that tumor-speci c mutations and mutations about the polymorphism of drug metabolism-related enzymes were discovered. The discovery can direct followup treatment.

Conclusion
Page 8/13 PT is a rare type of breast disease and easy to recur. Preoperative diagnosis of PT is di cult and pathological examination is the gold standard in the diagnosis of PT.

Consent for publication
The patient has given her written informed consent to publish her case including publication of images.

Availability of data and materials
The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.