The phyllodes menace—Variation in course, therapy, and appearance of phyllodes tumors in a case series of three patients

Abstract

Key Clinical Message

Early and complete surgical resection is the most important therapeutic and diagnostic measure. Adjuvant radiation is suggested for malign phyllode tumors, phyllode tumors larger than 10 cm or those with a low distance to the resection margins.

Abstract

Phyllodes tumors are rare fibroepithelial tumors of the breast. Histologically, they are usually classified as benign, borderline or malignant, though these classifications do not necessarily reflect the clinical course of the disease. These tumors may stay undetected for years, or show sudden and rapid progression. There is currently no consistent therapy recommendation based upon histological findings, the localization of the tumor and/or whether it is recurrent. Using the examples of three patients, we show how courses and therapy may differ widely, and discuss this in the context of the current state of the literature.

58 year old patient presenting with borderline phyllodes tumor.

1. INTRODUCTION

Phyllodes tumors (PT) are very rare fibroepithelial tumors of the breast. They are often misdiagnosed, or diagnosed late, which negatively affects both therapy and prognosis. Histologically, they can be classified into benign, borderline and malignant tumors (WHO‐classification) ¹ and while over 70% of the PTs are classified as benign, around 20% are classified as borderline, and less than 10% malignant. ² , ³ Malignant phyllodes tumors make up less than 1% of all female breast tumors, ⁴ with an incidence of around 2.1:1,000,000. ⁵ The peak occurrence is at the age of 35–55 years. ⁶ , ⁷ , ⁸ Recurrences are noted in around 13% of all patients. The ratio of recurrence rate of benign:borderline: malignant tumor is approximately 1:1.5:3. A five‐year survival rate was observed in almost 100% of patients with benign tumors, 98% with borderline, and around 88% with malignant. ³

Histologically, such tumors show biphasic lesions consisting of stromal and epithelial components. ⁹ , ¹⁰ Malignant tumors usually include rhabdomyosarcoma and liposarcoma rather than fibrosarcomas. ¹¹ , ¹² , ¹³ There is evidence for a genetic component in the development of PTs. Certain chromosomal alterations appear in both borderline and malignant PTs, but are absent in benign PTs. ¹⁴ , ¹⁵ Patients with Li‐Fraumeni syndrome (TP53 mutation) have an increased risk of developing phyllodes tumors. ¹⁶

Phyllodes tumors often grow rapidly and are usually painless. They are very hard to differentiate from a fibroadenoma using ultrasound or mammography. An ultrasound‐guided core biopsy is superior to a fine needle biopsy in confirming the diagnosis, but often does not allow for a reliable differentiation from fibroadenoma. Thus, open excision is recommended in most cases and is often the only therapeutic option. ¹⁷ There is currently no agreed upon therapeutic algorithm for the procedure which is dependent on the histological findings, the localization and the recurrence. The US American National Comprehensive Cancer Network (NCCN) recommends a resection distance of at least 1 cm regardless of the dignity of the tumor; the AGO (Gynecological Oncology Working Group) states that 0.5 cm is sufficient for borderline and malignant PTs. ¹⁸

In this article, the diversity in morphological appearances of PTs, their course and therapeutic concepts, including breast reconstruction are explored and discussed within the context of the current state of the literature.

2. CASE SERIES

Between June 2009 and December 2021, three patients suffering from PTs were treated at the Department of Plastic and Aesthetic Surgery, Hand Surgery, Helios Hospital Emil von Behring, Berlin, Germany. Written informed consent was obtained from the patient to publish this report. Patient 1 was treated within our department alone, while Patients 2 and 3 had primary resection and resection of recurrences at other hospital and were transferred to our department for further resection (in the case of an incomplete resection) and/or breast reconstruction. Thus, the data presented are not complete. Table 1 shows an overview of anamnestic patient data, specific tumor data and the therapy course of each patient (Figures 1, 2, 3). At the time of manuscript preparation, no patient had died and no further recurrence had occurred.

TABLE 1.

Overview of anamnestic patient data and specific tumor data.

	Patient 1	Patient 2	Patient 3
Anamnestic data
Age at first presentation	58 years	42 years	20 years
Gender	Female	Female	Female
Comorbidities	Hypothyreosis	Multiple fibroadenomas in right breast	None
Permanent medication	Thyronajod 125 mg	None	None
Family anamnesis about cancer	Negative	Negative	Negative
Age at first occurrence	53 years	Unclear (before the age of 38)	18 years
Other conspicuous findings	Thrombocytosis (858 G/l) and increased INR (1.3)	Multiple fibroadenomas in the right breast (multiple surgical resections in the past)	none
Tumor specific data
Primary tumor
Breast side	left	right	right
Classification	Borderline	Malign	Benign
Nodal status	inconspicuous	inconspicuous	inconspicuous
Type of malignancy (analogous to sarcoma classification of malignancy)	/	T4	/
Therapy
Surgery	Modified radical mastectomy Level I and II nodal clearance	NSSM, simultaneous breast reconstruction with implant	Tumor resection
Radiation	No	Yes (adjuvant)	No
Size, weight	350 × 280 × 180 mm, 7100 g	155 × 120 × 80 mm, 813 g	110 × 75 × 45 mm, *
Infiltrative growth	Yes	Yes	No
Macroscopic findings	Lobulated tumor, partly cystically configured, partly stringy, partly gelatinous and gray‐yellow	Lobulated tumor, partly cystically configured, partly stringy, partly gelatinous and gray‐yellow, necrosis	* (resection of primary tumor was not performed in our hospital)
Histological findings	Biphasic lesions Epithelioid‐mesenchymal neoplasm Many spindle cells Myxoid loosened stroma Atypical adipocytes	Biphasic lesions Epithelioid mesenchymal neoplasm Many spindle cells	Biphasic lesions Epithelioid‐mesenchymal neoplasm Many spindle cells Myxoid stromal component Atypical lipocytes
Minimal distances to the resection margins	3 mm (R0)	1 mm (R0)	Margins not clearly free of tumor
Recurrences	yes	no	yes
Number of recurrences	1 (since 10/2020)	0 (since 02/2021)	2 (since 06/2008)
Metastasis	Bone metastasis humerus (5 months after primary resection)	0	0
Recurrence   Time after first resection   Classification   Size   Therapy	4 months Malign (T4) 100 × 70 × 60 mm, 120 g ‐ Surgical resection ‐ Adjuvant radiation (in total 45,8 Gy)	/	1 year Borderline * Surgical tumor resection
Recurrence   Time after first resection   Classification   Therapy	/	/	9 months Borderline ‐ NSSM, simultaneous breast reconstruction with implant ‐ secondary autologous breast reconstruction (free FCI flap), 1 year later

Abbreviations: *, missing data; /, not applicable; g, gram; Gy, Gray; INR, international normalized ratio; l, liters; mm, millimeters; NSSM, nipple sparing subcutaneous mastectomy.

FIGURE 1.

Patient 1. (A,B) Patient 1 before surgical treatment; (C) macroscopic presentation of the PT indistinct lobulated tumor 335 mm on the cut surface. Cut surface partly cystic, partly stringy, gelatinous, gray‐yellow. (D) Overview, HE staining, Extensive necrosis (approx. 40%); (E) enlargement 10×, HE staining, malignant mesenchymal component with atypical spindle cells, moderate nuclear pleomorphism. (F) Enlargement 20×, HE staining, the mesenchymal part with heterologous component with abnormal adipocytes, brisk mitotic activity (HE staining; HPF = 0,45 mm) (HE = hematoxylin and eosin; HPF = high power field).

FIGURE 2.

Patient 2. (A) Macroscopic presentation of the PT; (B) enlargement 10×, HE staining, the mesenchymal hypercellular component, stromal spindle cells with enlarged, partly pin‐shaped, partly round‐oval, moderately pleomorphic nuclei, with evidence of nucleoli and numerous mitoses; (C) enlargement 20×; (D) Patient 2, 3 months after resection of PT and simultaneous reconstruction with a breast implant.

FIGURE 3.

Patient 3. (A) Patient 3 before resection of the second recurrence; (B) second recurrence after resection; (C) planning of the free FCI flap for autologous breast reconstruction, 1 year after NSSM and simultaneous breast reconstruction with implant; (D) 3 months after autologous breast reconstruction. (FCI flap, fasciocutaneous inferior gluteal artery perforator‐flap; NSSM, nipple sparing subcutaneous mastectomy).

3. DISCUSSION

As shown in this three‐case series, phyllodes tumors are highly variable in appearance, dignity, and progression. At times the challenge starts with the diagnosis, particularly as PTs can be very hard to differentiate from a fibroadenoma using ultrasound or mammography. ¹⁷ The criteria for the diagnosis and classification of PTs are summarized in the WHO recommendations for the classification of breast tumors and are based on the cell number of the stroma, cellular pleomorphism, ratio of epithelial structures, number of mitoses, invasive growth, and heterologous differentiation. ¹⁹ , ²⁰ Core biopsies often provide too little tissue for clear diagnosis, and therefore, a specimen excision is recommended when a PT is suspected. ¹⁷ Komenaka et al. studied 57 core biopsies where a diagnosis of PT was considered and found a 93% negative predictive value and 83% positive predictive value for core biopsy diagnosis of PT. ²¹ Thus, the histological differentiation between fibroadenoma and PT is challenging. As shown in this report, Patient 2 suffered from multiple tumors in the right breast and had multiple resections. Tumors had been rated as benign fibroadenoma for years until a malignant PT was diagnosed. It is unclear whether this was a misdiagnosis, a coincidence, or a malignant transformation. Furthermore, the histological classification of PTs into benign, malignant and borderline has not proven to be useful, as benign PTs are described as manifesting metastases, while cases with malignant PTs present an excellent prognosis. ²² , ²³ , ²⁴

Complete wide local surgical excision remains the standard therapy. ²⁵ Resection margins greater than 1 cm is often curative and reduces the risk of local recurrence. ²⁶ Minimal distances to the resection margins were not greater than 3 mm in the presented cases. Although is to say that these patients underwent a total mastectomy, so that minimal distance to the resection margins to the pectoralis muscle are, analogous to the guidelines of breast cancer, considered safe. In the case of PTs, the NCCN recommends a resection distance of at least 1 cm regardless of the dignity of the tumor and the AGO states that 0.5 cm is sufficient for borderline and malignant PTs. ¹⁸ However, there is currently no evidence about the relationship between the minimal distance to the resection margins and the recurrence rate. ²⁷ Some authors distinguish only between tumor‐free or non‐tumor‐free resection margins and make further treatment dependent on this. ²⁷ Asoglu et al. reported in a large retrospective multicenter study on malignant PT management that a 3 mm margin thresh‐old was adequate, with no impact of wider margins on overall survival, while they recommended re‐excision to obtain wider margins in cases with less than 3 mm margins. ²⁸

Two of the patients presented here had radiation as part of their course of therapy. The indication for radiation was the presence of a malignant PT. Patient 1 showed a borderline tumor at first occurrence and only had radiation when a malignant recurrence was present. Postoperative radiotherapy is a guideline‐based standard adjunctive treatment for patients with invasive breast cancer to prevent local recurrence and to improve disease‐free and overall survival. The need of adjuvant radiation therapy in PTs is still controversially discussed. There is consensus that benign tumors should be excised, but there are no data about additional radiation therapy. Although several studies have shown that additional radiation therapy of malignant PTs is associated with nearly halving the local recurrence rate. ¹⁸ For borderline and malignant tumors an analysis of cases collected from the Rare Cancer Network between 1971 and 2003 showed that adjuvant radiotherapy yielded superior 10‐year local control rates (86% with radiation versus 59% without radiation), but no survival benefit [20]. The NCCN guidelines (Version 1.2021) recommend adjuvant radiotherapy after primary resection only if additional recurrence would create significant morbidity, such as a chest wall recurrence following mastectomy. They generally advise additional radiotherapy for malignant phyllodes only in the case of local recurrence.

Finally, the role of adjuvant radiation therapy in the treatment of PTs is not clearly defined. Adjuvant radiotherapy should be considered in the cases of small resection margins or total mastectomy, especially tumors larger than 10 cm or in case of metastasis. Perhaps the recurrence in patient 1 could have been prevented if adjuvant radiation had been performed after resection of the first PT occurrence, even though the overall course would most likely not have been changed.

Other therapies, such as chemotherapy, preoperative chemoembolization and hormone therapy are described but considered obsolete. ¹⁰ , ²⁹ , ³⁰ , ³¹ , ³² , ³³

Axillary lymph node dissection shows no added benefit to recurrence or disease‐free survival in malignant PTs. Clinical lymphadenopathy is noted in 10%–15% of patients presenting with malignant PTs but is usually either related to tumor necrosis or to infected ulcerated skin lesions, with <1% pathological involvement. ³⁴ , ³⁵ Metastasis is predominantly hematogenous to the lungs, bones, and viscera. ¹⁸ , ²³

For phyllodes tumors, recurrence rates within the first 2–3 years of 10%–17%, 14%–25%, and 23%–30% are reported for benign, borderline and malignant tumors respectively. ¹⁷ The mean time to recurrence of benign, borderline, and malign PT's are reported as 20.2 ± 12.1, 16.9 ± 10.8, and 20.3 ± 19.0 months, respectively. ³⁶ Close follow‐up of these lesions is essential in order to identify recurrences. Again, there is no consistency in the literature regarding follow‐up intervals after surgery. ³⁶ , ³⁷ The indications range from once a year (ultrasound) for PTs with tumor‐free resection margins, whether benign or malignant, ²⁷ to 6, 12, 24 months, and then annually for 5 years if tumor‐free resection margins are greater than 1 cm. ³⁸

Table 2 summarizes the main characteristics of PTs, their therapy and follow‐up.

TABLE 2.

Summary of the characteristics of phyllodes tumors.

Incidence	‐Extremely rare
Imaging	‐Often not clear
Histology	‐Often not clear ‐Excision better than punch biopsy
Therapy	‐Surgical resection ‐Minimal distances to the resection margins > 0.5 cm or mastectomy
Recurrence	‐Frequent
Adjuvant radiation	‐Malignant PTs ‐Rapid growth ‐Size > 10 cm ‐Minimal distances to the resection margins < 0.5 cm
Follow‐up	‐At least once a year for the first 5 years

4. CONCLUSION

Phyllode tumors are rare tumors of the breast and should not be underestimated. The most important therapeutic and diagnostic measure might be early surgical resection. Adjuvant radiation is suggested for malign phyllode tumors, phyllode tumors larger than 10 cm or those with a low distance to the resection margins. Due to high recurrence rates, follow‐ups are recommended analogous to the recommendations of the breast cancer guidelines.

AUTHOR CONTRIBUTIONS

Daniel Schiltz: Conceptualization; visualization; writing – original draft. Alexander Jan Sokolow: Data curation; formal analysis; writing – original draft. Natalya Minck: Formal analysis; investigation; writing – review and editing. Stephan Schreml: Formal analysis; investigation; methodology; validation; visualization. Lutz Moser: Data curation; methodology; writing – review and editing. Uwe von Fritschen: Conceptualization; methodology; supervision; writing – review and editing.

FUNDING INFORMATION

No funding to declare.

CONFLICT OF INTEREST STATEMENT

Dr. Alexander Sokolow has no conflict of interest to declare in any of the products, devices, or drugs mentioned in this manuscript. Dr. Daniel Schiltz has no conflict of interest to declare in any of the products, devices, or drugs mentioned in this manuscript. Natalya Minck has no conflict of interest to declare in any of the products, devices, or drugs mentioned in this manuscript. Prof. Stephan Schreml has no conflict of interest to declare in any of the products, devices, or drugs mentioned in this manuscript. Dr. Lutz Moser has no conflict of interest to declare in any of the products, devices, or drugs mentioned in this manuscript. Dr. Uwe von Fritschen has no conflict of interest to declare in any of the products, devices, or drugs mentioned in this manuscript. None of the authors has a conflict of interest in any of the products, devices, or drugs mentioned in this manuscript.

ETHICS STATEMENT

Approved consent was obtained from all patients.

CONSENT

Written informed consent was obtained from the patient to publish this report in accordance with the journal's patient consent policy.

Schiltz D, Sokolow AJ, Minck N, Schreml S, Moser L, von Fritschen U. The phyllodes menace—Variation in course, therapy, and appearance of phyllodes tumors in a case series of three patients. Clin Case Rep. 2023;11:e7836. doi: 10.1002/ccr3.7836

DATA AVAILABILITY STATEMENT

The data that support the findings of this study are available on request from the corresponding author, [UvF].