Metaplastic Carcinoma

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 Metaplastic carcinoma is a well circumscribed tumor that consists of various combinations of poorly differentiated ductal adenocarcinoma, mesenchymal (sarcomatous) and other epithelial (eg, squamous cell) components

Whether these tumors have a worse prognosis than ordinary invasive ductal cancers is unclear. Some studies suggest that tumors in which the squamous cell component predominates are more aggressive and frequently treatment-refractory when compared to other infiltrating ductal cancers. However, because metaplastic breast cancer was not officially recognized as a distinct pathologic diagnosis until 2000, knowledge about treatment patterns and outcomes is limited.

The characteristics of 892 metaplastic breast cancers reported to the National Cancer Database between 2001 and 2003 were compared to those of 255,164 typical infiltrating ductal carcinomas. In contrast to patients with infiltrating ductal cancers, the following significant differences were noted in the group with metaplastic tumors:

  • Fewer T1 tumors (30 versus 65 percent)
  • More node-negative tumors (78 versus 66 percent)
  • More poorly-differentiated or undifferentiated tumor (68 versus 39 percent)
  • Fewer estrogen receptor-positive tumors (11 versus 74 percent).

Treatment outcomes were not reported.

Despite the perception of a worse prognosis, all metaplastic breast cancers are treated similarly to other invasive breast cancers.

Review

Metaplastic carcinomas represent a morphologically heterogeneous group of invasive breast cancers in which a variable portion of the glandular epithelial cells comprising the tumor have undergone transformation into an alternate cell type—either a nonglandular epithelial cell type (e.g., squamous) or a mesenchymal cell type (e.g., spindle, chondroid, osseous, myoid). Many reports have been published describing various aspects of metaplastic carcinomas, and many names have been applied to the various tumors comprising this group. No uniformly agreed upon classification scheme exists for these tumors, however. Metaplastic carcinomas are uncommon lesions, representing fewer than 5% of all breast cancers. The prognostic implications of a diagnosis of metaplastic carcinoma is difficult to define and may relate to some degree to the type of metaplasia present, as discussed below.

Clinical Presentation

Patients with metaplastic carcinoma are similar to patients with invasive carcinoma of no special type with regard to age at presentation, the manner in which the tumors are detected, and the location within the breast at which these tumors arise. Most patients present with a single palpable lesion that not infrequently is associated with rapid growth of short duration. In one study, skin fixation was noted in 9 of 26 patients (35%), and fixation to deep tissues was noted in 6 of 26 patients (23%).

The mammographic appearance of metaplastic carcinoma is not specific. Most are fairly circumscribed, noncalcified lesions, which in some cases appear benign. Some show both a circumscribed portion and a spiculated portion, which in one study correlated with the metaplastic and invasive epithelial components, respectively.Foci of osseous metaplasia may be detected mammographically in a subset of cases.

Gross Pathology

The gross appearance of metaplastic carcinomas is not distinctive, and these tumors can either be well circumscribed or show an indistinct or irregular border. Cystic degenerative changes are not infrequent, particularly in lesions with squamous differentiation. In general, metaplastic carcinomas tend to be relatively large tumors compared with invasive carcinomas of no special type, with a mean size of 3.9 cm (range 1.2 to 10 cm) reported in one study.

Histopathology

Microscopically, metaplastic carcinomas are highly distinctive but vary in the types and extent of metaplastic changes. Most reports divide metaplastic carcinomas into two broad categories: those that show squamous differentiation and those that feature heterologous elements, such as cartilage, bone, muscle, adipose tissue, vascular elements, and even melanocytes, among others  Investigators at the Armed Forces Institute of Pathology place metaplastic carcinomas into five categories: squamous cell carcinomas, spindle cell carcinomas, carcinosarcomas, matrix-producing carcinomas, and carcinomas with osteoclastlike giant cells, although others consider this last group a separate entity.

Squamous differentiation can range from well to poorly differentiated. In some tumors composed primarily of squamous cells, cystic degeneration is prominent. In such cases, parts of the tumor may be composed of squamous epithelial–lined cysts resembling benign epidermal inclusion cysts. Spindle cell differentiation is common in metaplastic carcinomas and is frequently seen in association with squamous differentiation. The term spindle cell carcinoma has been used by some investigators to describe metaplastic carcinomas in which the majority of the tumor shows this growth pattern.

The most common heterologous types of metaplastic carcinoma show chondroid or osseous differentiation . In these tumors, the cartilage and bone may appear histologically benign or frankly malignant, resembling chondrosarcoma and osteosarcoma, respectively. If the heterologous metaplastic component of a particular tumor predominates, the differential diagnosis must include a sarcoma, either primary or metastatic. Determining the correct diagnosis in such cases may require extensive tissue sampling to demonstrate epithelial elements. In some cases, immunohistochemical staining for epithelial markers such as keratin may be required for proper diagnosis. Although this is often helpful in tumors with spindle cell differentiation , not all metaplastic carcinomas show expression of epithelial markers, particularly those with heterologous differentiation. The results of immunohistochemical staining for other markers have been even more variable, and this subject has been reviewed in detail.Finally, ultrastructural analysis may be of value to demonstrate epithelial features that may not be evident on routine examination by light microscope.

One unusual subtype of metaplastic carcinoma, low-grade adenosquamous carcinoma, appears to represent a distinct clinicopathologic entity. These tumors are typically smaller than other metaplastic carcinomas, with a median size between 2.0 and 2.8 cm (range, 0.5 to 8.6 cm). They exhibit a firm yellow cut surface with irregular borders. Histologically, these tumors are well differentiated and show a peculiar collagenized, lamellated stroma. In most tumors, areas of squamous differentiation are admixed with areas of glandular differentiation . However, in some tumors, squamous differentiation can be quite limited in extent. The glands often show elongated, compressed lumens, which may suggest syringomatous differentiation. Microcysts filled with keratinaceous material may be present. DCIS is usually not seen. As discussed below, these lesions may be locally aggressive but have a relatively good prognosis when compared with other metaplastic carcinomas (see section Clinical Course and Prognosis).

The frequency of DCIS seen in association with metaplastic carcinoma varies among published reports. In lesions characterized by a prominent mesenchymal component in which a true sarcoma is in the differential diagnosis, the presence of DCIS argues in favor of metaplastic carcinoma.

Estrogen-receptor and progesterone-receptor studies in metaplastic carcinomas are typically negative, regardless of the histologic subtype examined. A review of the literature shows that only 13 of 115 metaplastic carcinomas (11%) were positive for estrogen receptors, and only 5 of 77 (6%) were positive for progesterone receptors.Using flow cytometry, Pitts et al. reported that six of eight metaplastic carcinomas (75%) were aneuploid or tetraploid. Similarly, using Feulgen-stained sections from 12 examples of metaplastic carcinoma, Flint et al. reported that the epithelial component demonstrated aneuploidy in all cases, and the mesenchymal elements were aneuploid in 11 of 12 (92%).230 In another study, 61% of metaplastic carcinomas with heterologous elements demonstrated p53 protein accumulation, and 11% demonstrated HER-2/neu overexpression.Drudis et al. reported that 46% of low-grade adenosquamous carcinomas overexpressed HER-2/neu, and 13% showed p53 protein accumulation.

Clonality in metaplastic carcinomas has been assessed using microdissection techniques and evaluation of loss of heterozygosity at multiple chromosomal loci. In that study, all six cases of metaplastic carcinoma demonstrated identical clonality of the epithelial and mesenchymal components, and the same clone was also identified in nearby DCIS in one case. The authors concluded that the mesenchymal component of these lesions arose from mutation of the epithelial component.

Clinical Course and Prognosis

The reported frequency of axillary lymph node metastases in patients with squamous or spindle cell carcinomas ranges from 6% to 54% of cases.In patients with metaplastic carcinoma with heterologous elements, lymph node metastases have been noted in 6% to 31% of cases.

In most cases, the routes of metastatic dissemination in metaplastic carcinomas are similar to those seen in breast cancers of no special type, including lymphatic spread to axillary lymph nodes rather than the hematogenous spread characteristic of mammary sarcoma. Metastatic lesions may demonstrate an epithelial phenotype, the metaplastic phenotype, or both.

Survival data reported in various studies are difficult to compare due to the relatively small numbers of patients included in the studies, differences in tumor types, differences in treatment and follow-up intervals, differences in the use of appropriate control groups, and paucity of studies that stratify patients by stage. Nevertheless, in patients with squamous or spindle cell carcinomas, reported overall survival rates have ranged from 43% to 86%. In patients with metaplastic carcinomas with heterologous elements, the reported overall survival rates range from 38% to 69%. One of these studies stratified patients by stage and reported that the overall survival rate at 5 years was 56% for stage I patients, 26% for stage II patients, and 18% for stage III patients. Chhieng et al. evaluated 32 patients with metaplastic carcinoma with heterologous elements, and follow-up information was available in 29 of these patients.The authors reported that metastases developed in six patients (21%) after an average follow-up of 6.25 years. The 5-year survival rate was 60%. The authors compared these patients with a control group of 112 patients with invasive ductal carcinoma matched for age at diagnosis, tumor size, and nodal status. Although patients with metaplastic carcinoma experienced a longer time to recurrence and a relatively better 5-year survival, the difference was not statistically significant.

In summary, the available data suggest that the prognosis for patients with metaplastic carcinoma is not appreciably different from that for patients with invasive carcinomas of no special type when tumor size and stage are taken into consideration. The one exception among the variants of metaplastic carcinoma that does appear to have prognostic implications is low-grade adenosquamous carcinoma. Among 16 patients with low-grade adenosquamous carcinoma who had lymph node dissections performed, only 1 (6%) had evidence of metastatic disease (in a single lymph node). Only 1 of the 43 patients included in both studies experienced distant metastases. In one study, however, four of eight patients treated with excision alone developed a local recurrence. In a second study, local recurrence after excision alone was seen in 5 of 19 (26%) patients. Unfortunately, details regarding the margin status in these lesions are not provided. Although it is possible that these lesions may be adequately treated with wide excision alone, the use of conventional local therapy for these patients until further data become available seems most prudent. The use of conservative surgery and radiation therapy for patients with other types of metaplastic carcinoma should also follow the same guidelines used for patients with conventional types of invasive breast cancer.

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