Accepted Manuscript

Title: Oral and maxillofacial metastasis of male breast cancer: report of a rare
case and literature review

Author: Nathalia de Almeida Freire, Bruno Augusto Benevenuto de Andrade,

Nathalie Henriques da Silva Canedo, Michelle Agostini, Mário José Romañach

PII: S2212-4403(18)30950-7
DOI: https://doi.org/10.1016/j.oooo.2018.05.006
Reference: OOOO 2011

To appear in: Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology

Received date: 3-4-2018

Revised date: 4-5-2018
Accepted date: 21-5-2018

Please cite this article as: Nathalia de Almeida Freire, Bruno Augusto Benevenuto de Andrade,
Nathalie Henriques da Silva Canedo, Michelle Agostini, Mário José Romañach, Oral and
maxillofacial metastasis of male breast cancer: report of a rare case and literature review, Oral
Surgery, Oral Medicine, Oral Pathology and Oral Radiology (2018),
https://doi.org/10.1016/j.oooo.2018.05.006.

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1 ORAL AND MAXILLOFACIAL METASTASIS OF MALE BREAST CANCER:

2 REPORT OF A RARE CASE AND LITERATURE REVIEW

4 Nathalia de Almeida Freire, DDS, MSca, Bruno Augusto Benevenuto de Andrade DDS,

5 PhDa, Nathalie Henriques da Silva Canedo, MD, PhDb, Michelle Agostini, DDS, PhDa,

6 Mário José Romañach, DDS, PhDa

a
8 Department of Oral Diagnosis and Pathology, Federal University of Rio de Janeiro,

9 School of Dentistry (UFRJ), Rio de Janeiro, Brazil.

b
10 Department of Pathology, Clementino Fraga Filho University Hospital, Federal

11 University of Rio de Janeiro, School of Medicine, Rio de Janeiro, Brazil.

12

13 Manuscript –1.988 words

14 Number of figures – 4; Number of tables – 1; Number of references – 19.

15 Conflicts of interest: Authors declare no conflict of interest.

16 Funding: No funding was received

17 Corresponding author:

18 Mario José Romañach, DDS, PhD

19 Department of Oral Diagnosis and Pathology, Federal University of Rio de Janeiro

20 School of Dentistry. Av. Carlos Chagas Filho 373, Prédio do CCS, Bloco K, 2° andar,

21 Sala 56. Ilha da Cidade Universitária, Rio de Janeiro/RJ. 21.941-902.

22 Phone: +55 21 39382087. E-mail: marioromanach@ufrj.br

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23 ABSTRACT

24 Oral and maxillofacial metastatic tumors are uncommon, with the breast, prostate, lung

25 and kidney representing the most common primary sites. Less than 1% of all breast

26 cancers occur in male patients, and to date, only eight cases of metastatic breast

27 adenocarcinoma to the oral and maxillofacial region in a male patient have been

28 reported in the literature. An 88-year-old male with previous history of a successfully

29 treated primary breast adenocarcinoma 12 years earlier was referred for evaluation of an

30 oral swelling lasting 6 months. Intraoral examination revealed a 2 cm reddish,

31 pedunculated nodule with a smooth surface located in the left retromolar region.

32 Imaging revealed maxillary sinus involvement. The patient was submitted to incisional

33 biopsy, and microscopic evaluation revealed invasive tumor islands compounded by

34 malignant epithelial cells, sometimes exhibiting ductal arrangement, which were

35 positive for the estrogen receptor and GCDFP-15. The final diagnosis was metastatic

36 breast adenocarcinoma. Breast metastases are exceedingly rare in the oral and

37 maxillofacial region of male patients; however, clinicians should consider breast

38 metastasis when evaluating reddish oral nodules in older patients, including men,

39 especially those with a history of malignancy.

40

41

42

43

44 Key words: Male breast cancer, Oral, Maxillofacial, Metastasis,

45 Immunohistochemistry.

46

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47 INTRODUCTION

48 Metastatic tumors in the oral and maxillofacial (OMF) region are uncommon.

49 These represent approximately 1% of all oral tumors, with the jawbones, particularly the

50 mandible, being more frequently affected than soft tissues.1-2 The clinical differential

51 diagnoses include common inflammatory and reactive lesions, and microscopic analysis

52 is usually required for diagnosis. This may be challenging, especially in patients with an

53 unknown cancer history.1-2 Patients with OMF metastases are usually treated by surgical

54 resection, which is sometimes combined with radiation therapy and/or chemotherapy. It

55 has poor prognosis, with an average survival period of 7 months.1-3 Malignant tumors

56 from almost any site can metastasize to the OMF region, the most common of which

57 originate from the breast, genital organs, kidney and colorectum for women, and from

58 the lung, kidney, liver and prostate for men.3-13

59 Male breast cancer (MBC) is a rare disease accounting for less than 1% of all

60 mammary malignancies.3 Our understanding of the epidemiology, treatment and

61 prognosis of MBC is still limited, with distant metastases usually observed in the bone

62 and lung.4 Breast metastasis to the OMF region in a male is an even rarer event, and to

63 the best of our knowledge, only eight cases have been published in the English-language

64 literature to date (Table 1).4-11 Herein, we describe an additional case of metastatic

65 MBC to the OMF region.

66 CASE REPORT

67 An 88-year-old male, originally from the Republic of Cabo Verde, presented

68 with a painless swelling in the left retromolar region lasting 6 months. His past medical

69 history included primary breast adenocarcinoma 12 years earlier in the left breast, which

70 had been successfully treated by surgery and axillary lymph node dissection, in addition

71 to a prostate carcinoma that had been surgically treated 6 years before. The patient

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72 reported hypertension and no history of tobacco or alcohol use, and his familial history

73 was deemed non-contributory. Extraoral examination showed slight asymmetry of the

74 left mid-face, with elevation of the nose wing. Intraorally, there was a well-

75 circumscribed, pedunculated, reddish nodule measuring 2 × 1 cm located between the

76 left buccal mucosa and retromolar region, which was covered by smooth mucosa

77 (Figure 1). The lesion was asymptomatic, fibroelastic in consistency, and there was no

78 hardening of surrounding tissues. Imaging revealed a hypodense expansile lesion in the

79 left maxillary sinus region, with cortical expansion of the orbital floor and destruction of

80 the nasal fossa and maxillary sinus cortices (Figure 2). Scintigraphy also revealed an

81 area of enhanced captation in the left maxillary sinus. Due to clinical suspicion of either

82 a sinonasal or oral squamous cell carcinoma or metastasis, an incisional biopsy was

83 performed under local anesthesia. Well-defined fibrous tissue was observed, which

84 exhibited an irregular cut surface with a whitish to brownish color (Figure 3).

85 Microscopic examination revealed proliferation of infiltrative tumor cells characterized

86 by an eosinophilic cytoplasm and hyperchromatic nucleus containing conspicuous

87 nucleoli which were organized in islands and nests, sometimes exhibiting ductal

88 arrangement with areas of comedonecrosis. Immunohistochemical staining revealed that

89 tumor cells were positive for the estrogen receptor in a nuclear pattern and gross cystic

90 disease fluid protein 15 (GCDFP-15) in the cytoplasmic granules, but were negative for

91 cytokeratin 7, cytokeratin 20 and prostate-specific antigen (PSA). The Ki-67 labeling

92 index was 30% (Figure 4). The final diagnosis was metastatic male breast

93 adenocarcinoma of the OMF region. The patient was referred to the oncology service

94 where he had previously been treated for primary breast cancer. Treatment with

95 hormone therapy was started involving Zoladex every 3 months and tamoxifen (20

96 mg/day). After 2 years of follow-up, the lesion had slightly decreased in size. The

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97 patient is clinically healthy, with no pain or any signs of fever, fatigue, weight loss or

98 prostration.

99 DISCUSSION

100 The incidence of MBC has increased significantly over the past two decades.

101 Although the etiology remains unknown, the risk factors that may predispose an

102 individual to breast cancer have been suggested to include diseases that alter the

103 estrogen–testosterone ratio in males. Men with Klinefelter syndrome have 50-times

104 higher risk and account for 3% of all MBC patients.9,14 Similarly, cirrhosis and

105 exogenous administration of estrogen (either in transgender individuals or as therapy for

106 prostate cancer) have been implicated as causative factors for MBC.3 Other risk factors

107 include mutations in the BRCA2 gene, exposure to radiation and a family history of the

108 disease.9,15 Interestingly, MBC accounts for up to 14% of all breast cancers in sub-

109 Saharan Africa, with the highest incidence observed in African-American men from the

110 United States. However, the specific factors responsible for the increased incidence in

111 Africans and African-Americans are not well understood.3 The present patient was

112 originally from the Republic of Cabo Verde, and had a past history of breast and

113 prostate cancers.3

114 Oral metastases are uncommon, generally affecting both men and women with

115 an overall median age of 60 years.13,16-19 The clinical signs and symptoms include

116 asymptomatic ulcerated swellings in the gingiva or tongue for soft tissue metastases,

117 and ill-defined radiolucent lesions in the posterior mandible for intra-osseous

118 metastases, which cause pain, paresthesia and numbness, as well as misleading

119 presentations such as toothache, dentoalveolar swelling and loose teeth.1,13 In men, oral

120 soft tissue and jaw metastases usually originate from the lung, prostate, kidney and

121 liver, and in women, from the breast, kidney, adrenal, genital organs (uterus, cervix,

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122 ovaries) and colorectum.19 Metastases to the nasal cavity and paranasal sinuses are rare,

123 and may represent the first manifestation of an otherwise clinically occult carcinoma,

124 mainly occurring in males with a mean age of 57 years.19 The main clinical features

125 include nasal obstruction, headache, painful facial swelling, visual disturbances,

126 exophthalmos, cranial nerve deficits and epistaxis.13 The most common tumor sites to

127 disseminate to this region are the kidney, lung, breast, thyroid and prostate. In the OMF

128 region, the maxillary sinus is most frequently involved, followed by the sphenoid,

129 ethmoid and frontal sinuses.19 The present case is a metastatic MBC with an epicenter in

130 the left maxillary sinus causing disruption to the lateral and inferior bone cortices, with

131 contiguous extension into the oral cavity and presentation as a reddish, polypoid

132 swelling in the retromolar region.

133 To the best of our knowledge, only eight cases of metastatic MBC to the OMF

134 region have been reported in the English-language literature (Table 1).4-11 The most

135 common clinical aspect reported in five cases was painful swelling that affected the

136 mandible, followed by involvement of the submandibular region, buccal mucosa and

137 masticator space, all reported in older men with median age of 66 years (ranging from

138 43 to 85 years).4-11 The primary tumor in the breast was already known before metastatic

139 spread in seven cases, and immunohistochemical studies were performed in only two

140 cases.4-11 The present case is the first description of metastatic MBC to the maxillary

141 sinus with oral involvement.

142 Ductal carcinoma, as observed in the present case, is the most prevalent

143 histopathological subtype, making up over 90% of all cases of MBC, followed by

144 mucinous, papillary and lobular subtypes.7,9 In addition to review of the clinical history

145 of the patient and histological evaluation of hematoxylin and eosin-stained sections,

146 immunohistochemical studies employing sensitive and specific antibodies may aid in

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147 identifying the primary site in a high percentage of metastatic cases.17 Breast

148 carcinomas usually stain positive for cytokeratin (CK) 7 and the estrogen receptor, and

149 are negative for CK20. Interestingly, the present case was positive for the estrogen

150 receptor but negative for CK7, a finding previously reported in MBC.7 Positive staining

151 for GCDFP-15 and negative staining for PSA confirmed the breast as the origin in the

152 present case.16-18

153 An interesting finding in the present case was the long time interval of 12 years

154 between the primary diagnosis of MBC and its OMF metastasis. Similarly, Gondim et

155 al.16 also observed that from 16 women with head and neck breast metastases, nine of

156 them were detected at a mean interval of 10.9 years after their primary breast cancer

157 diagnosis. Therefore, the long interval for metastasis of breast cancer to bone and other

158 organs such as lung and brain, as noted in women, it similar to the MBC metastasis to

159 the OMF region in the present case.16

160 Male breast cancer is thought to have a less favorable outcome when compared

161 to breast cancer in women, as it is usually more advanced and has a higher incidence of

162 lymph node metastasis.3 Although the outcome is usually poor, prognosis is dependent,

163 in part, on whether the oral or sinonasal metastasis is localized or part of widespread

164 disseminated disease. If the sinonasal metastasis is localized and treated aggressively,

165 average survival may be long. The present patient underwent a clinical check-up and

166 PET/CT scan which confirmed that the OMF metastasis was localized in the maxillary

167 sinus. Considering the advanced age of the patient, hormone therapy using Zoladex and

168 Tamoxifen was a conservative treatment choice in line with the wishes of the patient’s

169 family. The patient remains alive after 2 years of follow-up.

170 In summary, we present an exceedingly rare case of OMF metastasis of MBC,

171 the first case reported in Brazil. Clinicians and pathologists should be aware of the

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172 increasing incidence of MBC and its potential to develop late metastasis, particularly to

173 the OMF region. Careful correlation of clinical, microscopic and immunohistochemical

174 features are usually required for proper diagnosis of oral and sinonasal metastases.

175 REFERENCES

176 1. Hirshberg A, Shnaiderman-Shapiro A, Kaplan I, Berger R. Metastatic tumours

177 to the oral cavity - pathogenesis and analysis of 673 cases. Oral Oncol.

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181 3. Sandhu Nicole P, Bride Marie Brid Mac, Dilaveri Christina A, Neal Lonzetta,

182 Farley David R, Loprinzi Charles L, Wahner-Roedler Dietlind L, et al. Male

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184 4. Franklin CD, Kunkler IH. Carcinoma of the male breast metastatic to the

185 mandible. Clin Oncol (R Coll Radiol). 1992;4:62-3.

186 5. Choukas C, Toto PD, Choukas NC. Metastatic breast carcinoma mandible in

187 gynecomastia gynecomastic. Case report. Oral Surg Oral Med Oral Pathol.

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189 6. Morris PR, Prstojevich SJ, Hedayati P. Male breast cancer with maxillofacial

190 metastasis: case report. J Oral Maxillofac Surg. 2001;59:578-80.

191 7. Kesting MR, Loeffelbein DJ, Hölzle F, Wolff KD, Ebsen M. Male breast cancer

192 metastasis presenting as submandibular swelling. Auris Nasus Larynx.

193 2006;33:483-5.

194 8. Fontana S, Ghilardi R, Barbaglio A, Amaddeo P, Faldi F,Pericotti S. Male breast

195 cancer with mandibular metastasis. A case report. Minerva Stomatol.

196 2007;56:225-30.

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197 9. Gonzalez-Perez LM, Infante-Cossio P, Crespo-Torres S, Sanchez-Gallego F.

198 Mandibular metastases as first clinical sign of an occult male breast cancer. Int J

199 Oral Maxillofac Surg. 2012;41:1211-4.

200 10. Sahoo NK, Mohan Rangan N, Kakkar S, Jeyaraj P, Bhat S. Masticator space

201 metastasis from a male breast carcinoma: A case report. Journal of Oral and

202 Maxillofacial Surgery, Medicine, and Pathology. 2013; 25: 160–3.

203 11. Lee ZH, Lewing NW, Moak S, Friedlander PL, Chiu ES. Male breast cancer

204 metastasis to the oral mucosa and face. J. Plat Reconstr Aesthet Surg.

205 2014;67:277-8.

206 12. Maschino F, Guillet J, Curien R, Dolivet G, Bravetti P. Oral metastasis: a report

207 of 23 cases. Int J Oral Maxillofac Surg. 2013;42:164-8.

208 13. Servato JP, de Paulo LF, de Faria PR, Cardoso SV, Loyola AM. Metastatic

209 tumours to the head and neck: retrospective analysis from a Brazilian tertiary

210 referral centre. Int J Oral Maxillofac Surg. 2013;42:1391-6.

211 14. Fentiman IS. Male breast cancer is not congruent with the female disease. Crit

212 Rev Oncol Hematol. 2016;101:119-24.

213 15. Fentiman IS, Fourquet A, Hortobagyi GN. Male breast cancer. Lancet.

214 2006;367:595-604.

215 16. Gondim DD, Chernock R, El-Mofty S, Lewis JS. The great mimicker: metastatic

216 breast carcinoma to the head and neck with emphasis on unusual clinical and

217 pathologic features. Head Neck Pathol. 2017;11:306-13.

218 17. Gown AM, Fulton RS, Kandalaft PL. Markers of metastatic carcinoma of breast

219 origin. Histopathology. 2016;68:86-95.

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220 18. Darb-Esfahani S, von Minckwitz G, Denkert C, Ataseven B, Högel B, Mehta K,

221 et al. Gross cystic disease fluid protein 15 (GCDFP-15) expression in breast

222 cancer subtypes. BMC Cancer. 2014;14:546.

223 19. Barnes L. Metastases to the head and neck: an overview. Head Neck Pathol.

224 2009;3:217-24.

225

226

227

228

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229 Figure 1. Clinical features of oral and maxillofacial metastatic breast

230 adenocarcinoma in a male patient. (A) Scar from the mastectomy and axillary lymph

231 node dissection associated with primary breast carcinoma treatment. (B) Intraoral

232 examination revealed a well-circumscribed, pedunculated, reddish nodule measuring 2

233 × 1 cm, located at the transition between the left buccal mucosa and retromolar region

234 and covered by intact smooth mucosa.

235 Figure 2. Radiographic features of oral and maxillofacial metastatic breast

236 adenocarcinoma in a male patient. (A, B) Panoramic radiograph showing destruction

237 of the left nasal maxillary sinus cortices. (C) Cone beam computed tomography in the

238 coronal plane revealed a hypodense lesion in the left maxillary sinus with medial-lateral

239 and inferior-superior bone expansion, cortical expansion of the orbital floor and cortical

240 destruction of the nasal fossa and of the lateral cortex of the maxillary sinus. (D) Cone

241 beam computed tomography in the axial plane showed extension of the lesion to the

242 posterior region of the tuberosity.

243 Figure 3. Gross appearance of oral and maxillofacial metastatic breast

244 adenocarcinoma in a male patient, which appeared as a 2 × 1 cm well-circumscribed

245 nodule, fibrous in consistency, exhibiting irregular cut surface with a whitish to

246 brownish color.

247 Figure 4. Histopathological and immunohistochemical aspects of oral and

248 maxillofacial metastatic breast adenocarcinoma in a male patient. (A) Oral mucosa

249 fragment covered by parakeratinized, stratified squamous epithelium, with proliferation

250 and infiltration of tumor cells organized in islands and nests in the lamina propria

251 (hematoxylin and eosin [H&E], original magnification x100). (B) Tumor cells with

252 hyperchromatic nuclei, evident nucleoli and eosinophilic cytoplasm exhibiting a ductal

253 arrangement (hematoxylin and eosin [H&E], original magnification x200). A high-

11

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254 resolution version of these slides for use with the Virtual Microscope is available as

255 eSlide: VM04957. (C) Tumor cells were positive for estrogen receptor

256 (immunoperoxidase, original magnification x100) A high-resolution version of these

257 slides for use with the Virtual Microscope is available as eSlide: VM04959. (D) Tumor

258 cells were positive for GCDFP-15 (immunoperoxidase, original magnification x200). A

259 high-resolution version of these slides for use with the Virtual Microscope is available

260 as eSlide: VM04962.

261

262

263

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264 Table 1- Clinical features of 8 cases of oral and maxillofacial metastatic breast
265 adenocarcinoma in male patients reported in the English language literature and the
266 present case.

N Author Age Site Clinical features Breast cancer

history,
immunomarkers

1 Franklin & 52 Posterior Severe pain, Third Yes, Absent

Kunkler mandible molar was loose
(1992)4
2 Choukas et 43 Posterior Ulcerated swelling Yes, Absent
al. (1993)5 mandibular

3 Morris et al. 61 Anterior Soft tissue mass and Yes, Absent

(2001)6 submental hyperesthesia
triangle
4 Kesting et 86 Submandibular Painless mass Yes,
al. (2006)7 region Negative: ER, PR,
Her-2.
Positive:
Mammoglobin, E-
caderin
5 Fontana et 69 Mandible Multiple oral fistulae Yes, Absent
al. (2007)8 Osteolytic lesions

6 Gonzalez- 73 Posterior Painful swelling No, Absent

Perez et al. mandible
(2012)9
7 Sahoo et al. 60 Masticator Pain and limitation of Yes, Absent
(2012)10 space mouth opening

8 Lee et al. 85 Left buccal Hard fixed mass Yes,

(2014)11 mucosa and Negative:
cheek ER,PR,CK20.
Positive: CK7, Her-2
9 Present case 88 Left maxillary Asymptomatic Yes,
(2018) sinus and reddish nodule. Negative: CK7,
retromolar Destructive sinunasal CK20, PSA
region lesion Positive: ER,
GCDFP15
267 ER: estrogen receptor; PR: progesterone receptor; HER-2: Herceptin Receptor-2; CK:
268 Cytokeratin; PSA: prostate specific antigen; GCDFP15: Gross cystic disease fluid protein-15
269

270

271

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273 Figure 1A.tif

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276 Figure 1B.tif

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288 Figure 2D.tif

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291 Figure 3.tif

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300 Figure 4C.tif

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