Malignant Phyllodes Tumour with Liposarcomatous Differentiation, Invasive Tubular Carcinoma, and Ductal and Lobular Carcinoma In Situ: Case Report and Review of the Literature

A 43-year-old woman presented with a right breast lump that had enlarged over 5 months. She had chemoradiotherapy for non-Hodgkin's lymphoma in 1989. Histology revealed a malignant phyllodes tumour (PT) with liposarcomatous differentiation and ductal carcinoma in situ (DCIS) within the tumour with invasive tubular carcinoma, DCIS, and lobular carcinoma in situ in the surrounding breast. She had surgery and adjuvant radiotherapy. One year follow-up showed no recurrence or metastatic disease. Liposarcomatous differentiation is uncommon in PTs, and coexisting carcinoma is rare with 38 cases in 31 reports in the literature. Carcinoma is reported in malignant (n = 19), benign (n = 16) and in borderline PTs (n = 3) with invasive carcinoma (n = 18) and pure in situ carcinoma (n = 19) recorded in equal frequency. Carcinoma is more commonly found within the confines of benign PTs; whereas it is more often found surrounding the PT or in the contralateral breast in malignant PTs. Previous radiotherapy treatment is reported in only two cases. The aetiology of co-existing carcinoma is unclear but the rarity of previous radiotherapy treatment suggests that it is incidental. This case highlights the diverse pathology that can occur with PTs, which should be considered when evaluating pathology specimens as they may impact on patient management.


Introduction
Phyllodes tumors (PTs) of the breast are uncommon biphasic fibroepithelial neoplasms that account for <1% of all breast tumours. Most PTs are benign and carry a risk of local recurrence whereas malignant PTs have a 13% risk of haematogenous metastasis [1]. The distinction between benign, borderline and malignant PT is based on the assessment of a number of histological features including infiltrative margin, stromal overgrowth, stromal atypia, cellularity, and mitotic activity. However, while histological features are helpful, they are not accurate predictors of tumour behavior, and no single parameter is reliable in all cases [2].
PTs are believed to arise from intralobular or periductal stroma and may arise de novo or from pre-existing fibroadenomas [2]. Up to 30% of PTs show malignant transformation, most often in the form of malignant transformation of the stroma, which usually shows fibrosarcomatous differentiation and rarely heterologous sarcomatous elements. Malignant transformation of epithelial elements is very rare with only 38 cases reported in the literature. We present a case of a malignant PT that contained heterologous liposarcomatous stromal differentiation and exhibited a range of epithelial pathology. Ductal carcinoma in situ (DCIS) was present within the PT; DCIS, invasive tubular carcinoma, and multiple foci of lobular carcinoma in situ (LCIS) were noted in the adjacent breast tissue. Although it is generally accepted 2 Pathology Research International that the prognosis of a patient with a malignant PT depends on the nature of the PT, malignant epithelial components should, if present, be taken into account when managing the patient.

Case Report
A 43-year-old woman presented with a palpable lump in the central aspect of the left breast below the nipple. The lump was present for five months. It had increased in size over that time and was tender. Mammography showed a relatively well-circumscribed 3.4 cm mass in the lower central aspect of the breast ( Figure 1). An ultrasound-guided biopsy was performed and showed a fibroepithelial lesion with increased stromal cellularity and nuclear atypia, consistent with a PT. The patient had a history of non-Hodgkin's lymphoma involving the lumbar spine in 1989, which was treated with chemotherapy and radiotherapy to the lumbar area.
A wide local excision of the left breast was performed which was followed by a wider cavity excision and latissimus dorsi flap reconstruction. The patient was given adjuvant radiotherapy. The breast received 50.4 Gy at 1.8 Gy per fraction with a cone-down boost to the tumour bed, giving a total dose of 63 Gy to the area considered at the greatest risk of recurrence. Follow-up after one year showed no evidence of recurrence or metastasis. Axillary sampling was not performed but no axillary lymphadenopathy was identified at one year follow-up.

Pathological Findings
The wide local excision of the left breast, 75 × 60 × 30 mm, contained a well-defined, partly encapsulated tumor, 25 × 35 × 27 mm, with a papillary texture. A PT was confirmed histologically. The tumour showed the characteristic enhanced intracanalicular growth pattern with leaf-like projections into dilated cysts, extensive stromal overgrowth, and marked stromal hypercellularity (Figure 2(a)). Frankly malignant stromal features including nuclear pleomorphism and a high mitotic count (19 per 10 high power fields) were seen (Figure 2(b)). In many areas, liposarcomatous differentiation, characterized by pleomorphic lipoblasts, was present (Figure 2(c)). The margins of the PT were focally infiltrative. The epithelial component within the PT exhibited hyperplasia of usual type as well as foci of DCIS, intermediate grade, with cribriform and solid growth patterns, without necrosis ( Figure 2(d)). A small invasive carcinoma, 2 mm in size, was present at the periphery of the PT close to the deep margin of the specimen (Figure 3(a)). This was composed of well-formed tubules that lacked a myoepithelial layer (Smooth Muscle Heavy Chain Myosin and p63 negative) and was regarded as a grade 1 tumour [3] although it was too small to grade accurately based on the absence of sufficient high power fields for scoring of mitotic activity. Oestrogen receptor was strongly expressed and Her-2 was negative. The invasive tumour was adjacent to a small duct with morphological features of low-grade DCIS but there was no morphological transition between invasive carcinoma and the stromal or epithelial components of the adjacent PT. Multiple scattered foci of LCIS were also present peripheral to the PT, confirmed by downregulation of E-Cadherin staining (Figures 3(b) and 3(c)). The scattered nature of the LCIS precludes accurate measurement of its size.
The cavity re-excision specimen (190 g, 98 × 97 × 47 mm) included skeletal muscle and showed no residual PT. A single focus of DCIS, high-nuclear grade with comedonecrosis and microcalcification, 3 mm in size, was present within 1 mm to the medial margin ( Figure 3(d)). Multiple foci of LCIS were also noted.

Discussion and Review
Metaplastic change within PTs is uncommon. In the largest series of PTs reported, stromal metaplasia was present in only 11 of 335 cases, and malignant transformation of epithelium in the form of DCIS and LCIS was seen in only two cases [17]. Stromal changes included adipose and chondromyxoid elements and were seen in benign and borderline PTs whereas malignant heterologous elements were reported in malignant PTs. The latter was most commonly in the form of liposarcomatous differentiation [17,20,24,30,33,34], which does not equate with more aggressive clinical behavior [30,35]. Other forms of heterologous change are reported in PTs including osteosarcoma, rhabdomyosarcomas, leiomyosarcoma, rhabdomyosarcoma, and angiosarcoma [17,36]. Epithelial change in the form of usual-type epithelial hyperplasia is well recognized in PTs [17] but epithelial metaplasia is uncommon. Apocrine and squamous changes can occur but malignant epithelial transformation, as reported in the present case, is exceptionally rare. This case adds to the literature of 38 cases in 31 reports [1, of carcinoma arising either within and/or in association with PT (Table 1). It demonstrates the range of changes   that can be seen in association with a PT, including both liposarcomatous stroma and DCIS within the tumour and DCIS, LCIS, and invasive carcinoma in the peritumoural ipsilateral breast. Malignant epithelial elements are reported in all categories of PT. In situ and invasive carcinoma may involve the tumour itself and/or coexist with a PT elsewhere in the same or contralateral breast. Carcinoma is most commonly reported (n = 19) in malignant PTs. In the malignant PT category, carcinoma occurred more frequently in the ipsilateral [11,20,25,30,32] or contralateral [22,26,[29][30][31] breast rather than within the confines of the PT (n = 7) [17,21,23,24,27,28,33]. Coexisting carcinoma in malignant PTs is more commonly ductal (invasive ductal carcinoma, n = 6; DCIS, n = 10) than lobular phenotype (invasive lobular carcinoma, n = 2; LCIS, n = 4) [11,17,[19][20][21][22][23][24][25][26][27][28][29][30][31][32][33]. Heterologous stroma, most often liposarcomatous differentiation, was common in malignant PTs where carcinoma was also found (n = 8, 47%) [20,21,24,27,30,33]. From the available data, five patients with malignant PTs with coexisting carcinoma died from metastatic PT, between three months to 51 months after diagnosis [11,20,21,25,27], and one patient had metastatic carcinoma in two lymph nodes [19].
There are only three reports of carcinoma (DCIS) arising in association with borderline PT. Two patients had DCIS both within the PT and in the ipsilateral breast [11,18], one of whom died within three years from unrelated causes. In the other case, DCIS occurred in the ipsilateral breast at the time of diagnosis of a recurrent PT and death occurred from metastatic PT one year after the recurrence [18]. The molecular events involved in transformation and progression of PTs are largely unknown, and the rarity of coexisting epithelial malignancy makes it difficult to draw conclusions about the aetiological association between the carcinoma and PT in these cases. Genetic aberrations have been consistently demonstrated in PTs with increasing frequency from benign to borderline to malignant PTs. Most studies to date focused on stromal alterations and showed recurrent copy number gains and losses at +1q, −13q, −6q, +5, and −10p [37][38][39]. Where epithelium was evaluated separately, distinct molecular alterations were demonstrated in the Wnt2-APC-B-catenin pathway, and a role was postulated for both stroma and epithelium in the neoplastic process [40,41]. It is unclear, however, if the malignant transformation of epithelium results from stromal-epithelial interactions within the PT or if it represents cancerisation of a PT by carcinoma arising in the duct system peripheral to the PT. The latter may play a role in cases where carcinoma is present within the PT as well as peripheral to it in the ipsilateral breast. The finding of carcinoma in benign, borderline, and malignant PT and within fibroadenomas suggests that it is unlikely to be directly related to the number of genetic aberrations in the different categories of PT. A role of exogenous carcinogen exposure in malignant transformation merits consideration as an aetiological agent because two patients [10,20] in addition to the present case had a history of previous radiation. In all cases the radiotherapy field was remote from the breast which suggest that it is likely to be incidental.
The present case taken together with those in the literature demonstrates the diverse pathology that can be found with PTs, both within the tumour and in the surrounding and/or contralateral breast. The distinction between a malignant PT with coexisting carcinoma and a metaplastic carcinoma or carcinosarcoma should be considered in the diagnosis as these entities are managed differently and the distinction affects patient outcome. Carcinosarcomas have mixed malignant epithelial and stromal components with the latter showing no reactivity for epithelial immunohistochemical markers. While the present case fulfils these criteria, the characteristic leaf-like structure with malignant heterologous differentiation favours a diagnosis of malignant PT Pathology Research International 7 with coexisting carcinoma rather than a true carcinosarcoma. Carcinomas coexisting with PTs are generally diagnosed incidentally on the wide local excision, and the prognosis is dictated by the category of PT. In the present case, the malignant PT and not the carcinomatous elements will have the greatest impact on prognosis. However, the presence of coexistent carcinoma must be taken into account in management decisions, especially for benign and borderline PTs. Wider adequacy of excision of carcinoma, as in this case, and lymph node sampling should be considered.