—  SPECIALTY CONFERENCE  —

Breast Pathology

Case 1 - Low Grade (Fibromatosis-Like) Spindle Cell Carcinoma of the Breast

Nour Sneige
Anderson Cancer Center
Houston TX





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Clinical History:
The patient was a seventy-four year old woman who presented with a 1.3 cm left breast mass. Excisional biopsy was performed.


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Pathologic Findings:
On gross examination, the excised tumor was described as a circumscribed yellow white firm mass, with homogeneous gritty, grey-white cut surface.

Microscopically, the lesion is characterized by a proliferation of largely spindle/fibroblastic or stellate/myofibroblastic cell components of mild to moderate cellularity. The cells are dispersed individually and intermixed with various amounts of collagenous stroma, as well as form intersecting fascicle, focally suggesting a storiform pattern.Cell proliferation is bland and cellularity is 1+. Other areas show a loose myxoid matrix with inflammatory infiltrate, closely mimicking nodular fasciitis.

In addition to the spindle/stellate cell components, there are scattered foci with more fusiform cells with rounded nuclei and eosinophilic cytoplasm, raising the possibility of epithelial differentiation.

Differential diagnosis:
This is a spindle cell lesion with minimal cytologic atypia and characteristic cell arrangement. The differential diagnosis of spindle cell lesions of the breast includes: Fibromatosis like, fibromatosis, nodule fasciitis, inflammatory myofibroblastic tumors, reactive spindle cell nodules, low grade spindle cell sarcoma, and finally metastases. The work up of spindle cell lesions, in general, should include a panel of immunohistochemical staining for pancytokeratins including those which detect keratins 14, 17, and 34bE12. Almost all spindle cell carcinomas will be positive for at least one keratin. Whereas virtually all the tumors in the differential would be keratin negative.

1. Reactive spindle cell nodules of the breast after core biopsy or fine needle aspiration:
Gobbi and co-workers recently described 18 cases of reactive spindle cell nodules of the breast associated with a history of core biopsy or fine needle aspiration. In their study, the interval between the needle biopsy and subsequent excisional biopsy was available for 12 cases and ranged from 6 to 38 days (average, 16.4 days). The majority of which (15 cases) were associated with papillary lesions or complex sclerosing lesions. The nodules were non-encapsulated and relatively nodular measuring 1.5 to 9 mm. They were composed of interlacing fascicles of plump spindle cells, focally suggesting a storiform pattern, intermixed with thin-walled vessels and inflammatory cells, histiocytes, foam cells, and hemosiderin. The majority of the cases showed mild to moderate nuclear pleomorphism and low mitotic count. Immunohistochemically, the spindle cells were negative for AE1/AE3 and HMW keratin but expressed smooth and specific muscle actins, supporting a myofibroblastic condition.

2. Inflammatory myofibroblastic tumors:
Only rare cases have been reported in the breast. Tumors present as a palpable circumscribed firm mass and are composed of spindle cells with the morphological and immunohistochemical features of myofibroblasts, arranged in interlacing fascicles or in haphazared fasion, and variably admixed with an inflammatory component of lymphocytes, plasma cells, and histiocytes.

3. Fibromatosis of the breast:
is a rare locally aggressive lesion without metastatic potential originates from fibroblasts and myofibroblasts within the breast parenchyma. It is seen in women from13 to 80 years (average 46 and median 40) and is more common in the child bearing age than in perimenauposal and post menauposal patients. The lesion present as a solitary firm mass and mammographically is indistinguishable from carcinoma. They are poorly demarcated tumors measuring from 0.5 to 10 cm (average 2.5 cm). Mammary fibromatosis are histologically similar to those arising from the fascia or aponeurosis of muscles elsewhere in the body with the same immunophenotype. They are characterized by proliferating spindled fibroblasts and myofibroblasts forming sweeping and interlacing fascicles with varying amount of collagen deposition and cellularity. The periphery of the lesion reveals characteristic infiltrating finger-like projections entrapping mammary ducts and lobules. Immunoprofile: The spindle cells are vimentin positive, and a small proportion of them are also actin positive, while they are invariably negative for cytokeratin and S-100 protein. In a study of 33 cases, b-catenin was demonstrated in 82% of the cases.

4. Low grade spindle cell sarcoma and metastases:
In general, these lesions are very rare and should be diagnosed only after through sampling of the lesion fails to reveal any carcinoma Leiomyosarcomas are characterized by a strong diffuse reactivity for SMA and muscle specific actin, which is in contrast to the focal staining pattern observed for these markers in spindle cell carcinoma. Fibrosarcoma is more cellular and has a characteristic "herringbone "growth pattern of convincingly atypical spindle cells.

In spindle cell melanoma, because immunoreactivity for HMB 45 and Melan A can be negative in spindle cell melanoma, the presence of strong S100-protein would support that diagnosis over carcinoma.

5. Fibromatosis-Like Spindle Cell Carcinoma of the Breast, (FLSPCC):
Low grade (fibromatosis like) spindle cell carcinoma of the breast is a variant of metaplastic carcinoma that has recently been recognized as a distinct entity because of its resemblance to fibromatosis and similar propensity for local recurrence. In fact, some authors have chosen to avoid the term carcinoma, preferring fibromatosis-like tumor to emphasize its dominant phenotype (the major lesional component consists of spindle cells whereas less than 5% of the tumor is composed of epithelial elements or carcinoma) and its biologic behavior. FLSCC has only been reported in women, with a mean age of 64 years (range 40-85 years) at diagnosis. Tumors have ranged in size from 1 to 7 cm, and infiltrative margins are grossly present in 2/3 of the cases. Histologically, these tumors are composed of deceptively bland spindle cells arranged in intersecting fascicles of variable length and exhibiting low mitotic activity. A characteristic feature of FLSCC is the presence of epithelioid cells arranged in small cohesive aggregates or abortive tubules that are immunoreactive for keratin.

Immunophenotype: In the early studies of FLSCC, AEI/AE3 and HMWK were the most sensitive markers. Several recent studies, however, have suggested that some metaplastic carcinoma show myoepithelial differentiation. For example, Dune et al reported frequent expression of the basal cell and myoepithelial keratins 34 bE12, CK5, and CK 14. In a study of various subtype of metaplastic carcinoma, Reis-Filho et al, also found frequent positivity for SMA and CK 14, as well as immunoreactivity for S100 protein, p63, maspin and P-cadherin. Koker and Kleer reported expression of p63 in all 10 spindle cell metaplastic carcinomas examined, compared with only 1 of 174 (0.6%) nonmetaplastic breast carcinoma. In another study of 20 spindle cell metaplastic carcinoma, Leibl et.al., found positive staining for CD10, p63, SMA, and S100 in 80%, 70%, 60%, and 45% of cases, respectively, in addition to frequent immunoreactivity for CD29, and 14-3s delta (novel myoepithelial markers) and basal type keratin expression (34 bE12, CK5/6, CK14, and CK17). In the study by Carter et.al., pankeratin (MNF116) was the most sensitive (93%), followed by cytokeratin 14 (90%). CAM 5.2 (40%), and AE1/AE3 (41%) stained a much smaller proportion of cases. A subset of tumors (39%) showed evidence suggestive of myoepithelial differentiation, as exhibited by immunohistochemical staining for SMA, p63, and CK14. These findings support a myoepithelial immunophenotype, one could also make an argument that these more recent immuno data could equally support that at least some of these tumors are spindle squamous cell carcinomas.

Local recurrence is common in patients with FLSPCC treated with excisional biopsy only. In the series by Gobbi, et.al., 18 of the 30 patients for whom follow-up information was available (range, 6-88 months; medium, 27 months) 8 (26%) developed local recurrence within 5-72 months after the initial biopsy. Seven of those 8 women had been treated with excisional biopsy only. Nearly all recurrences were believed to be directly related to inadequate local excision.

In our series, the two cases of local recurrence occurred in patients who underwent local excision; although in one case the tumor was initially subjected to a wide local excision with wide free margins. None of the tumors in our series or in the series described by Gobbi, et.al., was associated with axillary lymph node metastasis. However, in our series distant metastasis were noted in two patients. The patient developed lung metastasis two years after the initial diagnosis. The lung metastasis exhibited similar histologic features to that of the breast primary.

In the series by Carter, et.al., 2 of the 6 (33%) low grade tumors with follow-up information died of metastatic disease within 12 and 25 month, 2 were alive with metastases 19 and 35 months and 2 were alive, with no evidence of disease (7-11 month).

In summary:
when confronted with a spindle cell neoplasm of the breast, a battery of cytokeratins should be performed, including those which detect keratins 14, 17 and 34bE12, because spindle cell carcinomas are far more frequently encountered than are primary spindle cell sarcoma of the breast. FLSCC of the breast have the potential for local recurrence and distant metastasis and should be treated accordingly. FLSPCC have a decreased rate of nodal involvement and the utility of axillary dissection without adenopathy is unclear, because the likelihood of lymph node metastasis is low.

Final Diagnosis:
Low Grade (Fibromatosis-Like) Spindle Cell Carcinoma of the Breast.

Key Words
Spindle cell lesions of the breast; Metaplastic spindle cell carcinoma; Fibromatosis-like tumors; Low grade fibromatosis like carcinoma.

References:
  1. Carter MR, Hornick JL, Lester S, Fletcher CD. Spindle Cell (Sarcomatoid) Carcinoma of the Breast. A Clinicopathologic and Immunohistochemical Analysis of 29 Cases. Am J Surg Pathol 2006;30(3):300-304.

  2. Sneige N, Yaziji H, Mandaville SR, et.al. Low-Grade (Fibromatosis-Like) Spindle Cell Carcinoma of the Breast. Am J Surg Pathol 2001;25(8):1009-1016.

  3. Gobbi H, Simpson JF, Borowsky A, Jensen RA, Page DL. Metaplastic Breast Tumors with a Dominant Fibromatosis-Like Phenotype Have a High Risk of Local Recurrence. Cancer 1999;85(10):2170-2182.

  4. Gobbi H, Tse G, Page DL, et.al. Reactive Spindle Cell Nodules of the Breast After Core Biopsy or Fine-Needle Aspiration. Am J Clin Pathol 2000;113:288-294.

  5. Gobbi H, Simpson JF, Jensen RA, MD, et.al. Metaplastic Spindle Cell Breast Tumors Arising within Papillomas, Complex Sclerosing Lesions, and Nipple Adenomas. Mod Path 2003;16(9):893-901.

  6. Davis WG, Hennessy B, Babiera G, Sneige N, et.al. Metaplastic Sarcomatoid Carcinoma of the Breast with Absent or Minimal Overt Invasive Carcinomatous Component. A Misnomer. Am J Surg Pathol 2005;29(11):1456-1463.

  7. Gilcrease MZ. Sarcomatoid Breast Tumors Have Sarcomatoid Behavior. Am J Surg Pathol 2007;31(2):326-327.

  8. Koker MM and Kleer CG. p63 Expression in Breast Cancer. A Highly Sensitive and Specific Marker of Metaplastic Carcinoma. Am J Surg Pathol 2004;28(11):1506-1512.

  9. Leibl S, Gogg-Kammerer M, Sommersacher A, et.al. Metaplatic Breast Carcinomas: Are they of Myoepithelial Differentiation? Immunohistochemical Profile of the Sarcomatoid Subtype Using Novel Myoepithelial Markers. Am J Surg Pathol 2005;29(3):347-352.