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Case Reports in Oncological Medicine
Volume 2014, Article ID 719061, 7 pages
http://dx.doi.org/10.1155/2014/719061
Case Report

Oral Metastasis of Metaplastic Breast Carcinoma in a Patient with Neurofibromatosis 1

1Stomatology Department, A.C. Camargo Cancer Center, Rua Professor Antonio Prudente 211, 01509-900 São Paulo, SP, Brazil
2Stomatology Department, University of São Paulo, Avenida Professor Lineu Prestes 2227, 05508-000 São Paulo, SP, Brazil
3Pathology Department, A.C. Camargo Cancer Center, Rua Professor Antonio Prudente 211, 01509-900 São Paulo, SP, Brazil
4Clinical Oncology Department, A.C. Camargo Cancer Center, Rua Professor Antonio Prudente 211, 01509-900 São Paulo, SP, Brazil

Received 25 February 2014; Accepted 9 April 2014; Published 30 April 2014

Academic Editor: Ossama W. Tawfik

Copyright © 2014 Ana Paula Molina Vivas et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Neurofibromatosis type 1 (NF1) has been associated with an increased risk for development of malignancy, especially malignant peripheral nerve sheath tumors. In addition, recently, literature has demonstrated an increased risk of breast cancer in women with NF1. The present paper shows a 53-year-old woman with NF1 who presented with metaplastic breast carcinoma and developed multiple metastases, including mandible. Furthermore, we reviewed the English literature, found 63 cases showing the association between NF1 and breast cancer, and added one more case. The present study demonstrated an important association between NF1 and breast cancer. Until the present time, there has been only one case of metaplastic breast carcinoma associated with NF1. Curiously, in our case the oral metastasis corresponded to sarcomatous component of metaplastic breast carcinoma.

1. Introduction

Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic disorder with a prevalence of 1 in 3500 people. This fully penetrant condition is characterized by multiple café au lait spots, axillary and inguinal freckling, cutaneous neurofibromas, and iris Lisch nodules [1, 2]. Less common manifestations include plexiform neurofibromas, optic nerve, and other central nervous system gliomas, scoliosis, tibial dysplasia, and vasculopathy. Additionally, patients with NF1 have increased relative risk of developing malignant peripheral nerve sheath tumors, leukemia, rhabdomyosarcoma, gastrointestinal stromal tumors, phaeochromocytoma, and breast cancer [38].

Metaplastic breast carcinoma (MBC) is uncommon, accounting for less than 5% of breast carcinoma [9]. This tumor consists of a heterogeneous group of malignancies which may correspond to mixed epithelial and sarcomatoid components, as well as primary squamous cell carcinoma, or mixed adenocarcinoma and squamous cell carcinoma [10]. Interestingly, there is only one case of MBC affecting a NF1 patient previously reported in the English literature [11].

The present study presents a rare case of a patient with NF1 who developed MBC, which metastasized to oral cavity. In addition, the importance of investigating breast tumors in NF1 patients is emphasized.

2. Case Report

A 53-year-old woman was referred to the Stomatology Department, complaining of teeth mobility and a swelling in her mouth with 10 days of evolution. During the anamnesis, the patient denied any alcohol consumption and related that she had smoked for 18 years and quit 4 years ago. Her medical history included NF1 and left mastectomy 20 days previously due to metaplastic carcinoma.

On physical examination, the patient had multiple café au lait macules and cutaneous neurofibromas located on cervical, dorsal, abdominal, and upper members (Figures 1(a) and 1(b)). The intraoral examination revealed a large mass with necrotic surface in the left retromolar area, measuring approximately 5 centimeters, which caused important trismus (Figure 1(c)). The main diagnostic hypothesis was metastasis of MBC. In addition, under local anesthesia, the patient underwent incisional biopsy.

fig1
Figure 1: (a) Abdominal surface presenting café au lait macules and multiple cutaneous neurofibromas. (b) Upper member with cutaneous neurofibromas. (c) Intraoral view showing an extensive tumor with necrotic surface located on the left retromolar area.

The histopathological analysis of the oral cavity lesion revealed a malignant neoplasia with spindle cell pattern and areas with osteoclast-like cells (Figures 2(a) and 2(b)) suggestive of metastasis of MBC. Subsequently, the specimens of mastectomy were reviewed. The epithelial component of breast tumor exhibited areas of in situ (Figure 2(c)) and invasive ductal carcinoma (Figure 2(d)) and also areas with squamous differentiation. However, the major part of the tumor was composed of a sarcomatoid component with areas of hemangiopericytic pattern (Figure 2(e)) and others with osteoclast-like cells (Figure 2(f)).

fig2
Figure 2: (a) Histological findings of malignant neoplasia of the oral cavity, showing atypical spindle cells with a storiform arrangement (H&E stain, ×40). (b) Areas with osteoclast-like cells (H&E stain, ×400). (c) Histological findings of metaplastic breast carcinoma with carcinoma in situ area beside the sarcomatous component (H&E, ×100). (d) Invasive ductal carcinoma (H&E, ×40). (e) Sarcomatoid pattern with hemangiopericytic area (H&E, ×40). (f) Sarcomatoid component with osteoclast-like cells (H&E, ×200).

On immunohistochemical analysis, the breast tumor cells (Table 1) were negative for estrogen and progesterone receptors and c-Erb-B2 was only positive in carcinoma in situ area. Vimentin was positive in the sarcomatous component, while cytokeratin AE1/AE3 and p63 were seen in few cells of the same component. Furthermore, S-100 and smooth muscle actin were positive in focal areas and CD68 was positive in osteoclast-like areas. A strong nuclear positivity was found against p53 and Ki-67 antibodies (Figure 3). The immunohistochemical analysis of the mandibular biopsy specimen (Table 1) showed similar findings to those of the breast tumor, except for total negativity of p63 and S-100. Considering the clinical, histopathological, and immunohistochemical features, the diagnosis of oral metastasis of the sarcomatous component of MBC was confirmed.

tab1
Table 1: Immunohistochemical features observed in both carcinoma and sarcomatoid components and in both breast and mandibular tumors.
fig3
Figure 3: Immunoreactivity of metaplastic carcinoma. (a) Strong immunoreactivity for vimentin in the sarcomatous component. (b) Immunoreactivity for cytokeratin AE1/AE3 is present in few cells of the sarcomatous component. (c) Reactivity for smooth muscle actin in focal area. (d) Immunoreactivity for CD68 in osteoclast-like cells. (e) Nuclear immunoreactivity for Ki-67. (f) Expression of p53 (polymer-HRP detection system, biotin-free).

The patient was referred to the Department of Clinical Oncology for evaluation. Computed tomography showed multiple lung and liver nodules and osteolytic lesion on the second costal arch. Moreover, all lesions were strongly suggestive of metastases. Chemotherapy with doxorubicin and ifosfamide was started but was interrupted due to pancytopenia. There was progression of the disease and the patient died 75 days after the diagnosis of oral metastasis.

3. Discussion

NF1 has been associated with cancer predisposition. The most common tumors are gliomas, malignant peripheral nerve sheath tumors, leukemia, and rhabdomyosarcoma [3, 20]. Although Brasfield and Das Gupta [12] reported in the 70s that 5 out of 54 women with NF1 developed breast carcinoma, only recently this association was recognized. Considering that breast cancer is already a common tumor in women, it would be difficult to know whether the coexistence of NF1 and breast cancer is a coincidence or a real predisposition. Sharif et al. [5] evaluated 304 women with NF1 and 14 had breast cancer (11 with infiltrating ductal carcinoma and 3 with infiltrating lobular carcinoma). Interestingly, these women had an early age of onset of breast cancer, with a median age of diagnosis of 44 years. Recently, Madanikia et al. [6] reviewed charts of 124 women with NF1 who were 20 years old or older and found 4 cases of breast cancer. Wang et al. [7] found 11 cases of breast cancer among a cohort of 76 women with NF1. Seminog and Goldacre [8] also showed a high risk of breast cancer, especially a threefold risk in women under 50. All these studies agree that women with NF1 are at higher risk for breast cancer than the general population, particularly when they are younger than 50 years old. Furthermore, these patients may have a delay in diagnosis since breast tumors may be misdiagnosed as NF1 manifestations [16, 17, 27]. In the present case, a 53-year-old woman with NF1 presented with a very aggressive breast cancer which metastasized to mandible, ribs, lung, and liver. Interestingly, on anamnesis, the patient related that she had undergone a mastectomy 20 days before, but she was being investigated due to breast nodule for 7 months.

We reviewed the English language literature and found 63 patients with NF1 who developed breast malignant tumors. Furthermore, most cases were ductal invasive carcinoma and less commonly lobular carcinoma (Table 2) [57, 1131]. Interestingly, we found one well-documented case of MBC (carcinosarcoma) [11]. In the present case, the patient presented with metaplastic carcinoma with very scarce epithelial component, with the major part of the tumor composed of a sarcomatoid component. The oral lesion was exclusively formed by sarcomatoid fraction.

tab2
Table 2: Total of patients with NF1 who developed breast carcinoma considering only English language literature.

Metaplastic carcinoma is a very rare type of breast cancer, which accounts for less than 5% of breast carcinomas [9]. It is a poorly differentiated tumor characterized by coexistence of adenocarcinoma with areas of matrix producing, spindle-cell, sarcomatous, and/or squamous differentiation. The present case showed wide undifferentiated spindle cell elements; areas of hemangiopericytic pattern and abundant osteoclast-like cells were also observed. In contrast, the epithelial component was the minor part formed by invasive ductal carcinoma and carcinoma in situ. In addition, overexpression of c-Erb-B2 in metaplastic carcinoma is rare (4%), while estrogen and progesterone receptors are frequently negative. Consequently, this tumor is usually referred to as “triple negative” [32, 33]. Similar to most cases previously reported in the literature, the present case exhibited a triple-negative immunoprofile and also had a high histological grade, which caused many anomalous immunoexpressions, such as focal positivity to SMA, S-100 antibodies, and coexpression of vimentin and CK AE1/AE3 (1% of the cells) in the sarcomatous component. In addition, p53 and Ki-67 markers showed high proliferative rate in both breast and mandible tumors (Table 1; Figures 2 and 3).

Metastatic lesions comprise 1% of all oral cavity malignancies and usually represent the evidence of wide spread disease. According to the review of Hirshberg et al. [34] the most common primary sites for oral metastases in women are breast, female genital organs, kidney, and colorectum, while in men they are lung, kidney, liver, and prostate. Still, this review showed that the mandibular bone is more frequently affected than the oral soft tissues in a proportion of 2 : 1, with the mandible being the most common location and the molar area the most frequently involved. In our case, we believe that the oral metastasis occurred in the gingiva, since there was rapid growth of the necrotic lesion and absence of specific symptoms such as pain and paresthesia. In addition, computerized tomography showed only a tumor mass emerging from the mandible without significant bone involvement. Other clinical findings of our patient included lung, bone, and liver metastases, which are the main sites of metastatic MBC [35]. Similar to our case, McMillan and Edwards [13] reported a case of bilateral mandibular metastases of breast carcinoma in a 41-year-old woman with NF1. It is noteworthy that the patient was only 27 years of age when she underwent a right radical mastectomy for removal of a breast carcinoma. Differently from our case, the oral lesion presented as a lump on the right jaw with an intact mucosa covering and the authors believed that the initial site of localization was within the bone.

Despite the follow-up of patients with NF1 and breast cancer, the literature data are not clear. Brasfield and Das Gupta [12] observed that all 5 patients died within 5 years of the diagnosis of breast cancer. This fact led them to question whether neurofibromatosis could influence the prognosis of patients with cancer. Nevertheless, some authors correlated the poor prognosis with late diagnosis since breast tumors may be misdiagnosed as NF1 manifestations as commented before [16, 17, 27]. Considering the 64 patients, information about follow-up was found in 36 patients. Of these, 17 are alive, 16 dead of breast cancer, and 3 dead due to other causes (Table 2).

In summary, since breast cancer has been associated in the literature with NF1, affected patients require screening for breast tumors. Thereby, early identification of breast cancer is important for appropriate management and better prognosis of the disease. Interestingly, the case presented here is the second reported in the English language literature referring to an MBC involving a woman with NF1, along with the curious finding that there was metastasis of the sarcomatous component to oral cavity.

Conflict of Interests

The authors declare that there is no conflict of interests regarding the publication of this paper.

References

  1. K. P. Boyd, B. R. Korf, and A. Theos, “Neurofibromatosis type 1,” Journal of the American Academy of Dermatology, vol. 61, no. 1, pp. 1–14, 2009. View at Publisher · View at Google Scholar · View at Scopus
  2. R. E. Ferner, “The neurofibromatoses,” Practical Neurology, vol. 10, no. 2, pp. 82–93, 2010. View at Publisher · View at Google Scholar · View at Scopus
  3. B. R. Korf, “Malignancy in neurofibromatosis type 1,” Oncologist, vol. 5, no. 6, pp. 477–485, 2000. View at Google Scholar · View at Scopus
  4. H. Brems, E. Beert, T. de Ravel, and E. Legius, “Mechanisms in the pathogenesis of malignant tumours in neurofibromatosis type 1,” The Lancet Oncology, vol. 10, no. 5, pp. 508–515, 2009. View at Publisher · View at Google Scholar · View at Scopus
  5. S. Sharif, A. Moran, S. M. Huson et al., “Women with neurofibromatosis 1 are at a moderately increased risk of developing breast cancer and should be considered for early screening,” Journal of Medical Genetics, vol. 44, no. 8, pp. 481–484, 2007. View at Publisher · View at Google Scholar · View at Scopus
  6. S. A. Madanikia, A. Bergner, X. Ye, and J. O. Blakeley, “Increased risk of breast cancer in women with NF1,” American Journal of Medical Genetics A, vol. 158, no. 12, pp. 3056–3060, 2012. View at Google Scholar
  7. X. Wang, A. M. Levin, S. E. Smolinski, F. D. Vigneau, N. K. Levin, and M. A. Tainsky, “Breast cancer and other neoplasms in women with neurofibromatosis type 1: a retrospective review of cases in the Detroit metropolitan area,” American Journal of Medical Genetics A, vol. 158, no. 12, pp. 3061–3064, 2012. View at Google Scholar
  8. O. O. Seminog and M. J. Goldacre, “Risk of benign tumours of nervous system, and of malignant neoplasms, in people with neurofibromatosis: population-based record-linkage study,” British Journal of Cancer, vol. 108, no. 1, pp. 193–198, 2013. View at Publisher · View at Google Scholar
  9. P. P. Rosen, RoSen's Breast Pathology, Wolters Kluwer, Philadelphia, Pa, USA, 3rd edition, 2009.
  10. G. M. Tse, P. H. Tan, T. C. Putti, P. C. W. Lui, B. Chaiwun, and B. K. B. Law, “Metaplastic carcinoma of the breast: a clinicopathological review,” Journal of Clinical Pathology, vol. 59, no. 10, pp. 1079–1083, 2006. View at Publisher · View at Google Scholar · View at Scopus
  11. I. Natsiopoulos, A. Chatzichristou, I. Stratis, A. Skordalaki, and N. Makrantonakis, “Metaplastic breast carcinoma in a patient with Von Recklinghausen's disease,” Clinical Breast Cancer, vol. 7, no. 7, pp. 573–575, 2007. View at Publisher · View at Google Scholar · View at Scopus
  12. R. D. Brasfield and T. K. Das Gupta, “Von Recklinghausen's disease: a clinicopathological study,” Annals of Surgery, vol. 175, no. 1, pp. 86–104, 1972. View at Google Scholar · View at Scopus
  13. M. D. McMillan and J. L. Edwards, “Bilateral mandibular metastases,” Oral Surgery Oral Medicine and Oral Pathology, vol. 39, no. 6, pp. 959–966, 1975. View at Google Scholar · View at Scopus
  14. M. D. El-Zawahry, M. Farid, A. A. El-Latif, H. Horeia, M. El-Gindy, and G. Twakal, “Breast lesions in generalized neurofibromatosis: breast cancer and cystosarcoma phylloides,” Neurofibromatosis, vol. 2, no. 2, pp. 121–124, 1989. View at Google Scholar · View at Scopus
  15. M. E. Zöller, B. Rembeck, A. Odén, M. Samuelsson, and L. Angervall, “Malignant and benign tumors in patients with neurofibromatosis type 1 in a defined Swedish population,” Cancer, vol. 79, no. 11, pp. 2125–2131, 1997. View at Google Scholar
  16. M. Nakamura, A. Tangoku, H. Kusanagi, M. Oka, and T. Suzuki, “Breast cancer associated with Recklinghausen's Disease: report of a case,” Archiv fur Japanische Chirurgie, vol. 67, no. 1, pp. 3–9, 1998. View at Google Scholar · View at Scopus
  17. Y. Murayama, Y. Yamamoto, N. Shimojima et al., “T1 breast cancer associated with von Recklinghausen's neurofibromatosis,” Breast Cancer, vol. 6, no. 3, pp. 227–230, 1999. View at Publisher · View at Google Scholar · View at Scopus
  18. M. Ceccaroni, M. Genuardi, F. Legge et al., “BRCA1-related malignancies in a family presenting with von Recklinghausen's disease,” Gynecologic Oncology, vol. 86, no. 3, pp. 375–378, 2002. View at Publisher · View at Google Scholar · View at Scopus
  19. D. Satgé, A. J. Sasco, D. Goldgar, M. Vekemans, and M.-O. Réthoré, “A 23-year-old woman with Down syndrome, type 1 neurofibromatosis, and breast carcinoma,” American Journal of Medical Genetics, vol. 125, no. 1, pp. 94–96, 2004. View at Google Scholar · View at Scopus
  20. Ş. Güran and M. Safali, “A case of neurofibromatosis and breast cancer: loss of heterozygosity of NF1 in breast cancer,” Cancer Genetics and Cytogenetics, vol. 156, no. 1, pp. 86–88, 2005. View at Publisher · View at Google Scholar · View at Scopus
  21. J. G. Posada and C. G. Chakmakjian, “Images in clinical medicine. Von Recklinghausen's disease and breast cancer,” The New England journal of medicine, vol. 352, no. 17, p. 1799, 2005. View at Google Scholar · View at Scopus
  22. L. Walker, D. Thompson, D. Easton et al., “A prospective study of neurofibromatosis type 1 cancer incidence in the UK,” British Journal of Cancer, vol. 95, no. 2, pp. 233–238, 2006. View at Publisher · View at Google Scholar · View at Scopus
  23. D. M. Hasson, S. Y. Khera, T. L. Meade et al., “Problems with the use of breast conservation therapy for breast cancer in a patient with neurofibromatosis type 1: a case report,” Breast Journal, vol. 14, no. 2, pp. 188–192, 2008. View at Publisher · View at Google Scholar · View at Scopus
  24. R. Invernizzi, B. Martinelli, and G. Pinotti, “Association of GIST, breast cancer and schwannoma in a 60-year-old woman affected by type-1 von Recklinghausen's neurofibromatosis,” Tumori, vol. 94, no. 1, pp. 126–128, 2008. View at Google Scholar · View at Scopus
  25. M. Alamsamimi, N. Mirkheshti, M.-R. Mohajery, and M. Abdollahi, “Bilateral invasive ductal carcinoma in a woman with neurofibromatosis type 1,” Archives of Iranian Medicine, vol. 12, no. 4, pp. 412–414, 2009. View at Google Scholar · View at Scopus
  26. L. Hegyi, K. Thway, R. Newton et al., “Malignant myoepithelioma arising in adenomyoepithelioma of the breast and coincident multiple gastrointestinal stromal tumours in a patient with neurofibromatosis type 1,” Journal of Clinical Pathology, vol. 62, no. 7, pp. 653–655, 2009. View at Publisher · View at Google Scholar · View at Scopus
  27. N. S. Salemis, G. Nakos, D. Sambaziotis, and S. Gourgiotis, “Breast cancer associated with type 1 neurofibromatosis,” Breast Cancer, vol. 17, no. 4, pp. 306–309, 2010. View at Publisher · View at Google Scholar · View at Scopus
  28. A. K. Bhargava, N. Bryan, and A. G. Nash, “Localized neurofibromatosis associated with chronic post-mastectomy lymphoedema—a case report,” European Journal of Surgical Oncology, vol. 22, no. 1, pp. 114–115, 1996. View at Publisher · View at Google Scholar · View at Scopus
  29. H. Takeuchi, S. Hiroshige, K. Hashimoto, T. Kusumoto, Y. Yoshikawa, and Y. Muto, “Synchronous double tumor of breast cancer and gastrointestinal stromal tumor in a patient with neurofibromatosis type 1: report of a case,” Anticancer Research, vol. 31, no. 12, pp. 4481–4484, 2011. View at Google Scholar · View at Scopus
  30. Y. Zhou, B. Pan, F. Mao et al., “A hidden breast lump covered by nipple appendices in a patient with von recklinghausen disease: a case report and review of the literature,” Clinical Breast Cancer, vol. 12, no. 1, pp. 71–75, 2012. View at Publisher · View at Google Scholar · View at Scopus
  31. B. Campos, J. Balmaña, J. Gardenyes et al., “Germline mutations in NF1 and BRCA1 in a family with neurofibromatosis type 1 and early-onset breast cancer,” Breast Cancer Research and Treatment, vol. 139, no. 2, pp. 597–602, 2013. View at Publisher · View at Google Scholar
  32. P. J. Barnes, R. Boutilier, D. Chiasson, and D. Rayson, “Metaplastic breast carcinoma: clinical-pathologic characteristics and HER2/neu expression,” Breast Cancer Research and Treatment, vol. 91, no. 2, pp. 173–178, 2005. View at Publisher · View at Google Scholar · View at Scopus
  33. J. D. Beatty, M. Atwood, R. Tickman, and M. Reiner, “Metaplastic breast cancer: clinical significance,” American Journal of Surgery, vol. 191, no. 5, pp. 657–664, 2006. View at Publisher · View at Google Scholar · View at Scopus
  34. A. Hirshberg, A. Shnaiderman-Shapiro, I. Kaplan, and R. Berger, “Metastatic tumours to the oral cavity—pathogenesis and analysis of 673 cases,” Oral Oncology, vol. 44, no. 8, pp. 743–752, 2008. View at Publisher · View at Google Scholar · View at Scopus
  35. H. N. Khan, L. Wyld, B. Dunne et al., “Spindle cell carcinoma of the breast: a case series of a rare histological subtype,” European Journal of Surgical Oncology, vol. 29, no. 7, pp. 600–603, 2003. View at Publisher · View at Google Scholar · View at Scopus