Contributed by Andrew Walls, MDDIAGNOSIS: METAPLASTIC CARCINOMA OF THE BREAST, SPINDLE CELL TYPE
Background
The term metaplastic carcinoma refers to a group of neoplasms that generally show a pattern of squamous, spindle cell, or mesenchymal differentiation, mixed with a component of adenocarcinoma, although the adenocarcinoma portion may be absent or minimal. This entity has been known historically by many different names, such as adenosquamous or spindle cell / sarcomatoid carcinoma, carcinosarcoma, and matrix producing carcinoma (1,2). They are rare neoplasms, accounting for less than 1% of all invasive breast carcinomas. The clinical presentation is similar to that of infiltrating duct carcinoma; however, microcalcifications are uncommon on mammography.
Because metaplastic carcinoma comprises a heterogeneous group of neoplasms, the pathology and prognosis may vary considerably. These tumors may show squamous differentiation, spindle cell areas, or even heterologous differentiation with chondroid or osseous metaplasia. The following discussion will focus on the spindle cell variant.
Diagnosis and Immunohistochemistry
Spindle cell carcinoma of the breast (SpCC) is characterized by a histology that shows a predominant spindle cell pattern. The spindle cells may be benign appearing, low-grade cells, or may have a high-grade, sarcomatoid appearance. Although ductal, lobular, and squamous patterns may also be present, sometimes there is a pure spindle cell pattern, and the diagnosis may be difficult by routine H&E, especially on needle core biopsies. The differential diagnosis includes other spindle cell lesions, such as primary sarcoma, nodular fasciitis, myofibroblastic lesions, Phyllodes tumor, and inflammatory pseudotumor (3).
Immunohistochemistry can be very helpful. A study by Adem, et al (4) suggests that some cytokeratin staining, such as AE1/3 and CAM 5.2, is variable, and therefore a wide-spectrum panel of keratins should be used. High molecular weight keratin has also been shown to be useful. (5) The spindle cells are generally positive for vimentin. S100 may be positive.
A recent development is the use of the nuclear antigen p63 as a sensitive and specific marker for metaplastic breast carcinoma. Koker and Kleer (6) examined 189 invasive breast carcinomas, which included 15 metaplastic carcinomas, 10 Phyllodes tumors, and 5 pure sarcomas for the pattern of p63 staining. They found that 13 of 15 (86.7%) of the metaplastic carcinomas strongly expressed p63, with 12 of 12 of the spindle cell variants expressing the marker. Only 1 of 174 (0.6%) nonmetaplastic carcinomas were positive for p63, and all Phyllodes tumors were negative. They report a sensitivity of 86.7% and specificity of 99.4% for p63 as a marker for metaplastic carcinoma, and the sensitivity as a marker for spindle cell variant in particular may be even higher.
Most studies report immunohistochemical staining for estrogen receptor (ER), progesterone receptor (PR) and Her-2/neu to be at most rarely positive (2, 7).
Behavior and Prognosis
The largest study of spindle cell carcinoma of the breast was by Wargotz et al, in 1988 (8). They examined 100 cases of SpCC, and found that of 47 patients with axillary dissection, only 6% had lymph node metastases. Distant metastases developed in 30 patients, and 29 (97%) of these died of their disease, whereas only 29% of patients with local recurrence died of disease. One caveat with this study is that a high percentage of the cases contained a conventional infiltrating ductal or intraductal component.
Two more recent studies have examined series of spindle cell carcinomas of the breast. As this entity is rare, the numbers of cases were small, but they nonetheless are an important attempt to further characterize the behavior of these tumors.
Khan et al (7) collected 19 cases of SpCC of the breast from a 15 year period. Six of the tumors contained a component of conventional carcinoma, usually infiltrating ductal. Fifteen of the tumors were high grade, and 4 were intermediate grade. The median age was 68 (range 27-92). Mean tumor size was 5.3 cm (range 1.6 - 20 cm). All cases were ER and PR negative, and one case was focally positive for Her-2/neu in the non-spindle cell component. Axillary lymph node involvement was seen in 6 of 15 cases (40%) that underwent a lymph node dissection. Median follow-up was 63.5 months. Six patients (32%) had local recurrence, 5 of whom went on to have metastatic disease. Overall, 11 patients (58%) developed metastatic disease, with the lung being the most common site, followed by bone and liver. Eleven patients (58%) died of breast cancer. Median survival was 18 months (range 4 - 109 months). Higher tumor grade correlated with poorer survival, but some patients with lower grade tumors also died of their disease.
Carter et al (2) studied 29 cases of SpCC of the breast from a 10 year period, 24 of which were consultation cases. All cases contained greater than 80% spindle cell component. Two cases contained a component of conventional invasive ductal carcinoma (15 % and 20%), and 4 separate cases showed ductal carcinoma in-situ. The cases showed a range of nuclear grade (7 low, 9 intermediate, and 13 high). The median age was 68 (range 40-96). Mean tumor size was 4.0 cm (range 1.5 - 15 cm). The study did not formally examine ER, PR or Her-2/neu status, but the authors report anecdotally that all cases were negative. Definitive axillary lymph node involvement was seen in only 1 of 20 cases (5%) that had axillary lymph node biopsies, and this patient had a tumor with 20% grade 3 invasive ductal component. Follow-up data for 24 of 29 patients were available for a median of 20 months (range 1-120 months). Three patients (13%) had local recurrence. Eleven patients (46%) developed metastatic disease, most commonly to the lung, followed by bone, pleura, mediastinum, liver and brain. Of these 11 patients, 6 had high-grade tumors, 2 intermediate-grade tumors, and 3 low-grade tumors. Ten of the 24 patients (42%) died of breast cancer. Median survival for these patients was 11.5 months (range 1-46 months).
Summary
Metaplastic spindle cell carcinoma of the breast is a rare primary epithelial breast tumor characterized by a predominantly spindle cell proliferation with a varying degree of adenocarcinoma and /or heterologous elements. It may be difficult to differentiate this lesion from other spindle cell lesions which may occur in the breast, especially on needle core biopsy, and therefore immunohistochemical staining with a broad spectrum cytokeratin is crucial for the diagnosis. A new immunohistochemical stain that has been shown to be sensitive and specific for this entity is p63. These tumors are almost uniformly ER, PR and Her-2/neu negative.
Because SpCC is such a rare entity, studies consist mostly of case series. These studies consistently find that SpCC's are larger at presentation than conventional invasive ductal carcinoma. Prognosis varies depending on the grade of the tumor, but even low-grade tumors seem to have the potential to cause metastatic disease and ultimately death. Studies have varied in the prevalence of axillary lymph node metastases, but nodal disease may be related to the amount of conventional invasive ductal carcinoma component present. Clearly a thorough sampling of the tumor on final resection is necessary to make a reasonable estimate of the prognosis.
REFERENCES
Contributed by Andrew Walls, MD
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