—  SPECIALTY CONFERENCE  —

Breast Pathology

Case 4 - Metaplastic Carcinoma Arising from a Phyllodes Tumor of the Breast

Fouad Boulos, American Univ/Beirut, Beirut, Lebanon





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Clinical History
67-year-old patient with a 6 cm right breast mass.


Case 4 - Figure 1
Phyllodes tumor with leaf-like architecture.
Case 4 - Figure 2
Transition between phyllodes tumor and metaplastic carcinoma (Low power).
Case 4 - Figure 3
Transition between phyllodes tumor and metaplastic carcinoma (Medium power).

Case 4 - Figure 4
Metaplastic carcinoma with squamoid island
Case 4 - Figure 5
Metaplastic carcinoma with diffuse growth and infiltration of fat.
Case 4 - Figure 6
Intersecting curvilinear fascicles of metaplastic carcinoma.

Case 4 - Figure 7
Metaplastic carcinoma with epithelioid tumor cells.
Case 4 - Figure 8
High power of metaplastic carcinoma with atypical mitosis, mild atypia, tearing artifact, and few inflammatory cells.
Case 4 - Figure 9
CK5/6 positivity in the metaplastic carcinoma

Introduction:
This case illustrates the rare but noteworthy potential of phyllodes tumors to harbor neoplasms of epithelial origin, and the clear potential to misdiagnose an epithelial spindle cell proliferation (metaplastic carcinoma) arising in a phyllodes tumor as originating from the phyllodal stroma.

Pathological/Microscopic Findings and any Immunohistochemical or Other Studies:
Sections show two morphologically distinct components. One component consists of a leaf-like biphasic proliferation typical of phyllodes tumor. The phyllodal stroma shows intermediate cellularity without significant atypia or pleomorphism, and the epithelium is bland and mildly hyperplastic, as is customary in phyllodes tumors. The second component consists of an overgrowth of spindle cells with mild typia, intersecting banana-shaped fascicles, and scattered mononuclear chronic inflammatory cells. Foci of necrosis were present but not extensive. The interface between the two components shows few squamoid islands. A histologically malignant adenocarcinomatous component was not present, but focally within the spindle cell proliferation, tumor cells acquired a slightly more epithelioid appearance with more rounded nuclei and clear to amphophilic cytoplasm. The spindle cell proliferation accounted for the majority of the mass and obscured the majority of phyllodal and non- phyllodal epithelial structures. Immunohistochemical analysis with antibodies against AE1/AE3 cytokeratin cocktail, CK5/6 and p63 were performed and showed diffuse and strong staining for CK5/6 and p63 while AE1/AE3 was patchy and weak. CD34 was negative in tumor cells.

Differential Diagnoses:
The main differential diagnosis in this case is a borderline or malignant phyllodes tumor. In the absence of an obvious phyllodes tumor component, the differential diagnosis would also include a variety of spindle cell lesions in the breast, such as fibromatosis, inflammatory pseudotumor, and nodular fasciitis, the characteristics of which are beyond the scope of this discussion.

Final Diagnosis:
Metaplastic carcinoma arising from a phyllodes tumor of the breast.

Case Discussion:
The association between metaplastic carcinoma and phyllodes tumors of the breast has only been reported in the literature on exceedingly rare occasions, essentially either as an isolated occurrence in a series describing metaplastic carcinomas [1], or as orphan case reports depicting squamous cell carcinomas (if one were to consider squamous cell carcinomas metaplastic) arising in phyllodes tumors [2, 3, 4, 5]. This paucity of cases is probably quite representative of the rarity of this event, but may also well be due to predictable under-recognition, given that one is much more likely to diagnose a malignant phyllodes tumor (mPT) with stromal overgrowth than a metaplastic spindle cell carcinoma arising in a phyllodes tumor (MCPT). Familiarity with certain morphologic clues and a high level of suspicion are therefore necessary to differentiate these similar yet biologically distinct neoplasms. The primary pathophysiologic difference between mPT and MCPT is that malignant phyllodes tumors derive from the phyllodal stroma, while metaplastic tumors arise from phyllodal epithelium. Morphologically, this results in subtle but recognizable differences.

Metaplastic carcinomas (especially of low and intermediate grades) arising in phyllodes tumors, have similar architectural features as usual metaplastic tumors of the breast. They include the hemi-storiform pattern with curvilinear intersecting fascicles, the diffuse "tearing" artifact around individual tumor cells and fascicles, and the occasional presence of epithelioid groups of tumor cells. [6, 7] These features become much less conspicuous when metaplastic carcinomas acquire a high grade sarcomatous phenotype, essentially rendering it indistinguishable from any undifferentiated sarcoma of mammary or extra-mammary tissues. [8] Additional clues that might help the pathologist suspect this process include the presence of fibrosclerotic foci with squamoid islands (FSIs) [7], and/or a neoplastic epithelial component i.e. ductal carcinoma in-situ (DCIS) within the epithelial compartment of the phyllodes tumor. FSIs are small groups of mildly atypical cells with eosinophilic cytoplasm and squamoid character, embedded in an active fibroblastic milieu. FSIs were initially linked to metaplastic carcinomas by Denley et al. who reported their presence in four low-grade and one high-grade metaplastic carcinoma arising within complex sclerosing lesions. [9] This finding was later corroborated by Gobbi et al who reported a series of 33 metaplastic tumors arising in association with papillomas, complex sclerosing lesions, and nipple adenomas, with additional emphasis on the consistent finding of squamoid islands within fibrosclerotic foci. [7] These squamoid islands, even when isolated in the re- excision specimen, were associated with recurrences in several cases as low-grade metaplastic tumors. [7] In phyllodes tumors, the presence of FSIs has so far not been documented, but has been noted in the experience of the breast consultation service at Vanderbilt University. Their presence has specifically been identified in all the MCPT, similar to what was reported for metaplastic tumors arising in complex sclerosing lesions. FSIs should of course be distinguished from biopsy site changes and reactive metaplastic alterations secondary to tissue displacement, ischemia and infarction. [10, 11, 12] Such a distinction is usually possible due to the additional overall changes that accompany squamoid metaplasia in these settings, such as the cell culture-like reactive fibroblastic proliferation, as well as the usual histiocytic reaction and hemosiderin pigment deposition. [10] Inevitably, some cases will have enough overlap to make a definitive call arduous, if not unrealistic.

The second clue is also related to the rare transformations of the phyllodal epithelium, from inconsequential squamous metaplasia [13], to neoplastic lesions such as in-situ carcinoma. [2, 14, 15, 16, 17, 18] DCIS is a frequent companion of metaplastic carcinomas, though not as persistently as with invasive no special type carcinoma. Davis et al documented DCIS in 10 of 22 metaplastic carcinomas in their series. [19] It is also generally implied that metaplastic carcinomas that lack any morphologic or immunohistochemical evidence of epithelial differentiation should be associated with an intraductal component, in order to comfortably make the diagnosis of metaplastic tumor. [8, 19] It therefore follows that a malignant phyllodes tumor harboring DCIS should certainly raise the suspicion for MCPT. Interestingly however, even in the MCPT that contains unequivocal DCIS (unpublished observation), squamoid foci are apparent upon close inspection of the neoplastic proliferation.

Once the diagnosis is suspected based on the aforementioned clues, confirmatory immunohistochemical studies are essential. As mentioned earlier, metaplastic carcinomas within phyllodes tumors will have the same histologic and immunohistochemical profiles as when they occur independently in the breast parenchyma. This would include positivity for high molecular weight and other cytokeratins, and for p63; hormonal receptors and Her2-neu are almost always negative. [1, 8, 20, 21] Other markers that may prove useful from a therapeutic standpoint include ones from the EGFR family, which have been noted in a significant portion of metaplastic tumors. [22]

Clinically, distinguishing these two entities is expected to be important, for prognostic and therapeutic considerations. Although the metastatic behavior of metaplastic tumors is comparable to that of malignant mesenchymal neoplasms and mPT in terms of their hematogenous pattern of distant spread, [19] metaplastic carcinomas are more aggressive tumors with high short-term mortality. This is occasionally true even for morphologically low-grade tumors. [8, 23, 24, 25] Also, while complete surgical excision is the mainstay of therapy for phyllodes tumors, a combination of surgery, chemotherapy, and radiation remains the treatment of choice for metaplastic tumors. [26] The final designation should therefore be specific as to the nature and grade of both processes in order to appropriately direct clinical management. It is not clear, at this point, whether the localization of the metaplastic tumor to the phyllodal environment would have an effect on its overall biologic behavior. Reports by Parfitt and Korula did show lymph node metastases from an invasive mammary carcinoma confined to a phyllodes tumor, questioning the theoretically protective nature of a preexistent confined environment. [15, 27]

We therefore assume that in the presence of expansile and infiltrative growth, the metaplastic tumor is to be regarded as if it were occurring outside the confines of a phyllodes tumor, and its prognosis and management should be assessed accordingly.

Conclusion(s):
Metaplastic spindle cell carcinoma arising in a phyllodes tumor is undeniably a very rare occurrence, but one that has potentially important prognostic and therapeutic implications. It is therefore prudent to keep this differential diagnostic possibility in mind, especially when faced with certain clues such as squamoid islands and DCIS within the phyllodal epithelial component.

References:
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