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Journal of Clinical Oncology, Vol 23, No 31 (November 1), 2005: pp. 7827-7835 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.00.9589 Squamous Cell Carcinoma of the BreastFrom the Departments of Breast Medical Oncology, Pathology, and Radiation Therapy, The University of Texas M.D. Anderson Cancer Center, Houston, TX Address reprint requests to Bryan Hennessy, MD, Dept of Medical Oncology, Box 10, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030; e-mail: bhennessy{at}mdanderson.org
PURPOSE: Squamous cell carcinoma (SCC) of the breast is rare and generally aggressive. In this study, we analyzed 33 patients treated at The University of Texas M.D. Anderson Cancer Center (Houston, TX) and a series of 137 patients identified through the Surveillance, Epidemiology, and End Results (SEER) database to make therapy recommendations. METHODS: Records of The University of Texas M.D. Anderson Cancer Center were searched for patients diagnosed with breast SCC from 1985 to 2001. All biopsy material was reviewed by a dedicated breast pathologist who performed immunohistochemistry for hormone receptors and the epidermal growth factor receptor (EGFR). We searched the SEER database for patients with breast SCC diagnosed between 1988 and 2001. RESULTS: We identified 33 patients with breast SCC, of whom two patients had metastatic disease at diagnosis. The median relapse-free survival (RFS) of 31 patients with localized disease was 20 months (range, 1 to 108 months), with a 26% RFS rate at 5 years. The median overall survival in these patients was 37 months (range, 12 to 108 months), with 40% surviving at 5 years. Median survival from the time recurrent disease was recognized was 14 months (range, 2 to 86 months). Tumors were usually hormone receptor–and HER2/neu-negative, though EGFR was frequently overexpressed. Information from the SEER database was consistent with most of our findings. CONCLUSION: SCC of the breast is aggressive and often treatment-refractory. The role of platinum salts, EGFR inhibitors, and other novel agents needs to be explored.
Squamous cell carcinoma (SCC) of the breast is an uncommon tumor that is diagnosed when more than 90% of the malignant cells are of the squamous type.1 It is rare, constituting less than 0.1% of all breast carcinomas.1 There are few reported series documenting the management and clinical outcome of these tumors.2 In a recent review of the literature, there was information about 92 cases of breast SCC, but the cases actually included a variety of histologic patterns in addition to SCC.2 Clinical and radiologic appearances are not specific, and tumors are usually hormone receptor–negative.3 The prognosis for this type of breast cancer is still a subject of controversy: some reports suggest that it is aggressive, with an outcome comparable to that of poorly differentiated breast adenocarcinoma.2-8 As a result of lack of data, the issue of whether to prescribe adjuvant treatment for SCC remains unresolved.4 To help settle these controversies, we studied clinical and pathologic features, management, and outcome of SCC of the breast in a series of 33 women treated at The University of Texas M.D. Anderson Cancer Center (Houston, TX) and in a series of 137 patients identified through the Surveillance, Epidemiology, and End Results (SEER) database. We conclude that SCC of the breast is an extremely aggressive disease and that better systemic treatment is required to prevent recurrence. The frequent expression of epidermal growth factor receptor (EGFR) in this disease requires further study and may constitute a potential therapeutic target to be exploited, possibly in association with platinum-based treatment.
M.D. Anderson Cancer Center Patients The M.D. Anderson Institutional Computerized Database was searched to identify patients with a diagnosis of SCC of the breast who were evaluated and treated here. Thirty-three patients were identified. The patients had a median age of 52 years (range, 32 to 71 years). Their medical records were retrospectively reviewed to obtain demographic, clinicopathologic, treatment, and outcome information. Details regarding patient characteristics, surgical treatment, radiotherapy, and chemotherapy were also gathered from the medical records. All patients were confirmed to have SCC of the breast after systematic review of the pathologic material at our institution by a breast pathologist. The diagnosis of primary SCC of the breast is made in the absence of an associated primary SCC in a second site and in the absence of skin involvement. There must be a clear predominance (> 90%) of areas with SCC at histologic examination. All patients in our series fit these criteria. Tumors were classified and staged according to clinical and pathologic information. Nineteen patients had modified radical mastectomy, 13 patients had segmental mastectomy and axillary dissection (followed by adjuvant radiotherapy in 12 patients: 50 Gy to the breast [nine patients] and axilla [three patients] with a 10-Gy boost to the breast), and one patient experienced disease progression during neoadjuvant chemotherapy and radiation therapy, precluding surgery. For patients who were treated with chemotherapy for metastatic disease, their response status was classified on the basis of standard criteria.9 Our pathologist (S.K.) reviewed all tissue samples and performed immunohistochemical analysis to determine the estrogen receptor (ER) status, the progesterone receptor (PR) status, and the EGFR status of 21 samples. Immunohistochemical staining was performed on 4-µm sections cut from a representative paraffin block of the invasive squamous carcinoma of the breast. Immunostaining was performed on a Dako autostainer (Dako Corp, Carpinteria, CA) with the LSAB-2 peroxidase kit (Dako Corp), with 3,3' diaminobenzidine used as the chromogen. Primary antibodies were used against the following: ER (6F11, Novocastra Laboratories Ltd, Newcastle upon Tyne, United Kingdom), PR (Ab-9, NeoMarkers/Lab Vision Corp, Fremont, CA), HER2/neu (NeoMarkers/Lab Vision Corp), and EGFR (Zymed Laboratories Inc, South San Francisco, CA). Nuclear staining of more than 10% of tumor cells was considered to indicate ER and PR positivity. Membranous staining of more than 10% of tumor cells was regarded as indicating HER2/neu and EGFR positivity. The immunoreactivity for HER2/neu was confirmed by fluorescence in situ hybridization analysis of the HER2/neu gene copy number. We used the path vision HER2/neu kit (Vysis Inc, Downers Grove, IL), which uses two directly labeled fluorescent DNA probes, one specific for the HER2/neu gene focus and the second specific for the alpha satellite DNA sequence at the centromeric region of chromosome 17. Signals for 60 tumor cells were counted by using an epifluorescence microscope, and the ratio of HER2/neu to chromosome 17 was calculated. A ratio of more than 2.0 was considered to represent HER2/neu gene amplification and regarded as a positive result.
SEER Patients
Data Analysis
The characteristics of the 33 M.D. Anderson patients are summarized in Table 1. We performed immunohistochemistry and/or fluorescence in situ hybridization for HER2/neu overexpression subject to availability of tissue blocks (n = 25). EGFR overexpression was examined in immunohistochemistry studies in 21 tumor samples.
Disease Extent Two (6%) of the 33 M.D. Anderson patients had distant metastases (stage IV) at diagnosis (Table 1 and Fig 1). The majority of patients (69%) had stage II disease at diagnosis. Sixteen (52%) of 31 patients with localized disease at diagnosis had node-positive tumors.
Locoregional Control, RFS, and OS Ten of the 33 M.D. Anderson patients had breast surgery here (Table 2 and Fig 1). In those with localized disease at diagnosis, adjuvant radiation therapy was administered to 19 patients (61%); seven patients were treated with radiation therapy here. Twelve patients (39%) experienced locoregional relapse; of these, four relapses occurred in the ipsilateral breast, six relapses occurred in the chest wall, one relapse occurred in the ipsilateral axilla, and one relapse occurred in the contralateral supraclavicular fossa. Of the 12 patients with a locoregional relapse, five patients had undergone an initial segmental mastectomy and axillary dissection, followed by adjuvant radiotherapy in four patients (the other patient refused radiotherapy), and seven patients had an initial modified radical mastectomy, followed by adjuvant radiotherapy in two patients. Of the six patients with local relapse who had been given adjuvant radiotherapy, four suffered a locoregional relapse within the irradiated field; of these, two patients had prior adjuvant radiotherapy to the breast (50 Gy with a 10-Gy boost) after segmental mastectomy, and two patients had prior modified radical mastectomy and adjuvant radiotherapy (50 Gy in 25 fractions to the chest wall and 46 Gy in 23 fractions to the supraclavicular fossa and axilla in one patient and 60 Gy to the chest wall and axilla in the other patient). The 5-year locoregional RFS was 56%. Of the 12 patients with a locoregional relapse, systemic metastatic disease was diagnosed simultaneously in six patients. Eight patients experienced locoregional relapse and were treated with surgery and/or radiation; six of these patients have died of systemic metastatic disease. Of the 12 patients with locoregional relapse, four patients were initially treated with chemotherapy. The reason for the high locoregional relapse rate is not clear, although five patients had positive surgical margins, and one patient elected to have alternative therapy after surgery for an ulcerating tumor. Seven of the patients with locoregional relapse had stage II disease, four patients had stage III disease, and one patient had stage I disease initially. The disease relapsed locally in two patients while they were receiving adjuvant chemotherapy.
The median RFS of the 31 patients without metastatic disease at diagnosis was 20 months (range, 1 to 108 months), with a 26% relapse-free at 5 years (Fig 2A). The median OS of these patients was 37 months (range, 12 to 108 months), with 40% surviving at 5 years (Fig 2B). The projected 10-year OS rate was 26%. Survival was not associated with age, race, or type of surgery (segmental v modified radical mastectomy; Table 2). The stage of disease at diagnosis was significantly associated, as expected, with OS, but not with RFS, because of the small patient numbers (Table 2).
Relapse After a median follow-up of 50 months (range, 10 to 108 months), 22 (71%) of 31 patients with localized disease initially have suffered relapse. The median survival from the recognition of recurrent or metastatic disease was 14 months (range, 2 to 86 months).
Systemic Therapy
The median RFS of the 24 patients treated with chemotherapy in the neoadjuvant or adjuvant setting was 23 months (range, 1 to 108 months), and the median OS was 42 months (range, 10 to 108 months). Thirteen of these patients had node-positive disease. The median RFS of the seven patients with no distant metastases at diagnosis who did not receive adjuvant or neoadjuvant chemotherapy was 14 months (range, 4 to 74 months), and the median OS was 37 months (range, 10 to 74 months). Three of the seven patients had node-positive disease. There was no significant difference in the RFS or OS rates between the patients treated with adjuvant or neoadjuvant chemotherapy and those not treated (P = .615 and .503, respectively). Two patients had limited metastatic disease at diagnosis. After a modified radical mastectomy, one of these patients was treated with anthracycline-based chemotherapy, followed by cisplatin/fluorouracil and then docetaxel, and subsequently underwent resection of lung metastases. This patient is currently alive and relapse free at 86 months after diagnosis. The other patient suffered relapse with systemic metastases at 18 months despite having undergone a modified radical mastectomy and liver resection followed by anthracycline-based chemotherapy and high-dose chemotherapy that included paclitaxel. Twenty-two patients with localized disease experienced relapse; as mentioned, six patients had a locoregional recurrence alone, but only two of these patients have remained free of systemic metastases. One of these two patients was treated with excision and radiation therapy and is relapse free 85 months later, whereas the other patient is currently receiving docetaxel/carboplatin chemotherapy after excision of local recurrence. The remaining 20 patients were treated with various chemotherapy regimens for metastatic disease, including anthracyclines, platins, taxanes, capecitabine, vinorelbine, trastuzumab, and bexarotene, but only three patients (15%) had a partial response to therapy, and three patients (15%) had stabilization of disease (Table 4).
Hormonal Therapy Four patients were treated with tamoxifen as adjuvant treatment. All four patients had ER-positive tumors, and two patients also had PR-positive tumors. Two of the patients are currently alive and relapse free. Tamoxifen was used in two patients with metastases, one of whom had an ER-positive tumor. Neither patient responded to the drug.
Radiotherapy Ten patients received radiation therapy for recurrent disease. Three patients had more than one site irradiated. All patients experienced a partial response or symptomatic improvement, but in four patients, disease progression occurred within the irradiated site (two locoregional, one lung, and one leptomeningeal) at a mean of 6 months later.
Receptor Status of the Tumor
SEER Database
SCC of the breast was first reported in 1908 by Troell.10 It is thought to arise directly from the epithelium of the mammary ducts, although an alternate theory is that the tumor arises from foci of squamous metaplasia within a preexisting adenocarcinoma of the breast.11 The mean age at presentation is 54 years.12 The diagnosis of primary SCC of the breast can only be made in the absence of an associated primary SCC in a second site and in the absence of skin involvement.13,14 There must be a clear predominance (> 90%) of areas with SCC at histologic examination. Breast SCCs are generally large (usually > 4 cm) at presentation and cystic in more than 50% of cases.6 SCC of the breast is an aggressive malignancy with a poor outcome. The outcome of patients with localized breast SCC registered in the SEER database between 1988 and 2001 was somewhat better than in our study, though their outcome was still poor overall (64% 5-year OS rate), particularly for patients diagnosed with stage III disease. A review of the literature reveals that the prognosis of this type of breast cancer is still regarded as somewhat controversial, though many studies suggest that it is an aggressive disease that may behave like poorly differentiated breast adenocarcinoma.1-3,5-9,15-18 Table 6 shows that the outcome of M.D. Anderson Cancer Center and SEER patients with SCC of the breast is generally inferior to the outcome of all breast cancer patients registered in the SEER database between 1988 and 2001. It also seems that SCC of the breast is at least as aggressive as grade 3 hormone receptor–negative adenocarcinoma, using data for the latter disease from www.adjuvantonline.com.19 Although data from the SEER database are consistent with our findings of a poor prognosis, it is not clear why outcomes reported in the SEER database are better than those in our series. Factors that may explain this difference include tertiary referral center bias and perhaps more accurate histologic diagnosis (or perhaps different criteria for pathologic diagnosis) at a specialized center. It is also possible that SEER database patients have less complete follow-up. In addition, more of the SEER database patients were diagnosed with stage I disease.
In our series, regional lymph node metastases were present in 50% of patients at diagnosis of SCC of the breast. This is in contrast to a lower frequency of nodal metastases in some reports, which is supported by information from the SEER database.2,6,7,13,20 Consistent with other reports, our study and SEER data showed that breast SCC is usually a high-grade and hormone receptor–negative tumor.2,6,7 There is insufficient evidence about the activity of endocrine therapy for SCC, but it is reasonable to use endocrine treatment for patients with ER- and/or PR-positive SCC. HER2/neu is also usually not overexpressed or amplified in this disease. The high frequency of EGFR positivity is interesting and may be exploited in the development of future treatments for this disease. Although by definition SCC of the breast is diagnosed when there is a clear predominance of areas of SCC, the disease probably represents a continuum with varying degrees of squamous metaplasia within adenocarcinoma rather than an entity entirely separate from invasive ductal carcinoma.7 This is supported by the findings of Stevenson et al,20 who found that when tumors identified as pure SCC on light microscopy were subjected to ultrastructural analysis, either separate squamous and glandular cells were present or both histologic features were noted to coexist in cells. We therefore speculate that differences in patient characteristics seen in different studies are in part related to differences in the diagnostic criteria for SCC. Current breast cancer chemotherapy regimens clearly have limited activity in breast SCC. This has been reported previously.2,17 However, in a case report of one patient with breast SCC, no residual invasive SCC or metastatic nodal disease was found after neoadjuvant cisplatin/fluorouracil.18 This patient was free of recurrence at last follow-up. We treated five patients with neoadjuvant chemotherapy and saw no responses. In our series, of the two patients treated with platinum-based therapy in the adjuvant setting and one patient received cisplatin-based therapy with resection of metastatic disease, two patients are currently alive and relapse free. Platinum-based regimens had some limited activity in patients with metastases. It may be prudent to initiate adjuvant radiation therapy earlier than usual for breast cancer because of the tendency for locoregional relapse. However, because locoregional relapse occurred frequently within an irradiated field (four of 19 treated patients), it seems that SCC of the breast is often relatively radioresistant. In addition, four patients in the M.D. Anderson Cancer Center series who experienced a locoregional relapse had either T1N0 or T2N0 tumors. Thus the suitability of breast SCC patients with small tumors for breast conservation should be considered carefully. Because our series is small and patient treatment heterogenous, we cannot draw definitive conclusions regarding best systemic therapy. However, the poor outcome of patients with conventional breast cancer chemotherapy suggests that the role of EGFR inhibitors with platinum agents and taxanes in the adjuvant treatment of this disease needs to be explored in an attempt to improve outcomes. In addition, combinations of chemotherapy and/or EGFR inhibitors administered concurrently with radiation have been shown in human SCCs of other anatomic sites to minimize the risk of locoregional recurrence.21,22 Recently, the use of gene profiling has allowed us to identify a number of subtypes of breast cancer, each with differences in prognosis and therapy responsiveness.23 The basal form of breast cancer is associated with aggressive behavior and poor survival. This type of breast cancer is thought to arise from basal progenitor cells in the ductal epithelium of the breast.24,25 There are many similarities in the clinical behavior of this breast cancer subtype and breast SCC; it is thus reasonable to suggest that breast SCC actually belongs to this basal group of breast cancers, originating from a progenitor cell in the breast with a degree of maturational plasticity.26 The application of gene profiling to SCC of the breast will clarify this. Study of SCC of the breast for basal or myoepithelial markers will help clarify the origin of this rare form of breast cancer and may help us better understand mechanisms of carcinogenesis. In conclusion, breast SCC is an extremely aggressive disease associated with frequent locoregional and distant relapses and resultant deaths. Better systemic therapy is therefore needed to improve patient outcomes. The role played by EGFR and its various signaling pathways in this disease needs to be studied to clarify its potential as a treatment target. The use of anti-EGFR therapy, together with synergistic cytotoxics such as platinums and taxanes, should be explored in a clinical trial. Biologic studies of these rare breast tumors are urgently needed to determine the reasons for chemotherapy resistance and to find other relevant treatment targets.
The authors indicated no potential conflicts of interest.
Supported by the Nellie B. Connally Breast Cancer Research Fund and Cancer Center Support Grant No. P30 CA016672 29 from the National Cancer Institute. Authors’ disclosures of potential conflicts of interest are found at the end of this article.
1. Rosen PR: Rosen’s Breast Pathology. Chapter 19. Philadelphia, PA, Lippincott Williams & Wilkins, 2001, p. 455-461, 1997 2. Behranwala KA, Nasiri N, Abdullah N, et al: Squamous cell carcinoma of the breast: Clinico-pathologic implications and outcome. Eur J Surg Oncol 29:386-389, 2003[CrossRef][Medline] 3. Tayeb K, Saadi I, Kharmash M, et al: Primary squamous cell carcinoma of the breast: Report of three cases [French]. Cancer Radiother 6:366-368, 2002[Medline] 4. Menes T, Schachter J, Morgenstern S, et al: Primary squamous cell carcinoma (SqCC) of the breast. Am J Clin Oncol 26:571-573, 2003[Medline] 5. Moisidis E, Ahmed S, Carmalt H, et al: Primary squamous cell carcinoma of the breast. ANZ J Surg 72:65-67, 2002[Medline] 6. Cardoso F, Leal C, Meira A, et al: Squamous cell carcinoma of the breast. Breast 9:315-319, 2000[Medline] 7. Lafreniere R, Moskowitz LB, Ketcham AS: Pure squamous cell carcinoma of the breast. J Surg Oncol 31:113-119, 1986[Medline] 8. Cornog JL, Mobini J, Steiger E, et al: Squamous carcinoma of the breast. Am J Clin Pathol 55:410-417, 1971[Medline] 9. Husband JE, Schwartz LH, Spencer J, et al: Evaluation of the response to treatment of solid tumours: A consensus statement of the International Cancer Imaging Society. Br J Cancer 90:2256-2260, 2004[Medline] 10. Troell A: Zwei Falle von Palttenepithelcarcinom. Nord Med Ark 1:1-11, 1908 11. Farrand R, Lavigne R, Lokich J, et al: Epidermoid carcinoma of the Breast. J Surg Oncol 12:207-212, 1979[Medline] 12. Toikkanen S: Primary squamous cell carcinoma of the breast. Cancer 48:1629-1632, 1981[CrossRef][Medline] 13. Weigel RJ, Ikeda DM, Nowels KW: Primary squamous cell carcinoma of the breast. South Med J 89:511-515, 1996[Medline] 14. Sheen-Chen S, Chen Y, et al: Primary squamous cell carcinoma of the breast. South Med J 85:207-209, 1992[Medline] 15. Jin Y, Campana F, Vilcoq JR, et al: Primary epidermoid carcinoma of the breast. Clinical, histopathologic and prognostic study of 14 patients. [French]. Bull Cancer 79:675-679, 1992[Medline] 16. Wargotz ES, Norris HJ: Metaplastic carcinomas and sarcomas of the breast. Am J Clin Pathol 96:781, 1991[Medline] 17. Rostock RA, Bauer TW, Eggleston JC: Primary squamous carcinoma of the breast: A review. Breast 10:27-31, 1984 18. Dejager D, Redlich PN, Dayer AM, et al: Primary squamous cell carcinoma of the breast: Sensitivity to cisplatinum-based chemotherapy. J Surg Oncol 59:199-203, 1995[Medline]
19. Ravdin PM, Siminoff LA, Davis GA, et al: Computer program to assist in making decisions about adjuvant therapy for women with early breast cancer. J Clin Oncol 19:980-991, 2001 20. Stevenson JT, Graham DJ, Khiyami A, et al: Squamous cell carcinoma of the breast: A clinical approach. Ann Surg Oncol 3:367-374, 1996[Medline]
21. Vokes EE, Kies MS, Haraf DJ, et al: Concomitant chemoradiotherapy as primary therapy for locoregionally advanced head and neck cancer. J Clin Oncol 18:1652-1661, 2000 22. Bonner JA, Giralt J, Harari PM, et al: Cetuximab prolongs survival in patients with locoregionally advanced squamous cell carcinoma of head and neck: A phase III study of high dose radiation therapy with or without cetuximab. J Clin Oncol 22:5507, 2004
23. Sorlie T, Perou CM, Tibshirani R, et al: Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci U S A 98:10869-10874, 2001 24. Chang CC, Sun W, Cruz A, et al: A human breast epithelial cell type with stem cell characteristics as target cells for carcinogenesis. Radiat Res 155:201-207, 2001[CrossRef][Medline]
25. Nielsen TO, Hsu FD, Jensen K, et al: Immunohistochemical and clinical characterization of the basal-like subtype of invasive breast carcinoma. Clin Cancer Res 10:5367-5374, 2004
26. Korbling M, Estrov Z: Adult stem cells for tissue repair: A new therapeutic concept? N Engl J Med 349:570-582, 2003 Submitted December 17, 2004; accepted June 13, 2005.
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
